Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same

ABSTRACT

Compounds represented by formula (Ia) are disclosed by the invention, along with compositions and complexes thereof, optionally in combination with compounds of formula (Ib). Pharmaceutical formulations and methods of making and using such compounds are also disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The instant application is a continuation-in-part of U.S.application Ser. No. 09/519,976 filed Mar. 7, 2000, each of claimspriority to U.S. Provisional Application Serial No. 60/150,878 filedAug. 26, 1999, the disclosures of which is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

[0002] The invention generally relates to novel pharmaceutically activecompounds, compositions comprising the same, pharmaceutical formulationsof the same, methods of making the same, and methods of using the same.

BACKGROUND OF THE INVENTION

[0003] Various compounds used in inhibiting gastric acid secretion areknown in the art and include a class of benzimidazole-substitutedcompounds, one of which is omeprazole. Omeprazole is currentlycommercially available in tie formulation PRlLOSEC®. In particular, U.S.Pat. No. 4,255,431 proposes such benzimidazole-substituted compoundsgenerally described by the formula (III) in tire '431 patent thatallegedly encompasses omeprazole. Various methods of making thesecompounds are also proposed in the '431 patent

[0004] European Patent No. 0 124 495 B1 proposes various salts ofomeprazole, namely alkaline salts of the formula (I) in the '495reference which includes lithium, sodium, potassium, magnesium, andcalcium salts, along with methods of making the salts. The methods offorming these salts may involve employing a hydroxide, alkoxide, oramine base, or cation exchange using a metal salt

[0005] Erlandsson, P., et al. J. Chromatography, 632 (1990) pp. 305-319propose separating the (−) and (+) enantiomers of omeprazole utilizingchromatographic techniques. In this publication, the separation isproposed to take place on a preparative scale using a cellulose-basedchiral phase, e.g., trisphenyl-carbamoyl cellulose coated on3-aminopropyl silica. It is appreciated that other schemes and processesare available for this. separation.

[0006] PCT Publication No. WO 94/27988 proposes salts of the singleenantiomers of omeprazole and methods of making the same. The processinvolves separating the two stereoisomers of a diastereomer mixture ofan acyloxymethyl-substituted benzimidazole compound described by theformula (IV) set forth in this published application, followed bysolvolysis of each separated diastereomer in an alkaline solution. Saltsof the single enantiomers are formed and isolated by neutralizingaqueous solutions of the salts of the single enantiomers of omeprazolewith a neutralizing agent PCT Publication No. WO 96/02535 proposes aprocess for the enantioselective synthesis of single enantiomers ofomeprazole or its alkaline salts. The process employs an oxidizing agentand a chiral titanium complex which may include a titanium(IV) compound.

[0007] PCT Publication No. WO 98/54171 proposes the magnesium salt ofthe (−) enantiomer of omeprazole. The '171 publication also proposes amethod of synthesizing the above magnesium salt as well as the potassiumsalt of (−) omeprazole that may be used as a suitable intermediate forpreparing the magnesium salt. The potassium salt is taught to be usefulin treating gastrointestinal diseases.

[0008] U.S. Pat. No. 54,386,032 to Brändström propcses an improvedmethod for synthesizing omeprazole which involves reacting5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl-thio]-1Hbenzimidazole with m-chloroperoxybenzoic acid in a methylene chloridesolution.

[0009] The teachings regarding the methods of making omeprazole asreferred to in these references, salts thereof, enantiomers thereof, andsalts of the enantiomers, as well as formulations which may includethese compounds, all rely on the chemical structure of omeprazole beingaccurately determined and the referenced compound or compounds beingconsistently prepared using the referenced techniques. Morespecifically, a methoxy group on the benzimidazole ring has beenexplicitly stated in the literature to be present at the 5-position, inomeprazole, a racemic mixture, and an optically pure isomer ofomeprazole designated as esomeprazole or s-omeprazole. Applicants havenow unexpectedly discovered the complexity of omeprazole and therelative bioactivity of each of its previously undiscovered andundisclosed attributes. More specifically, Applicants have confirmedthat the methods of the prior art do not yield a single compound havingthe methoxy group in the 5-position on the benzimidazole ring aspreviously taught, nor do all of the methods of the prior art yieldconsistent results. In fact, omeprazole as conventionally referred to asa bulk drug substance (in its solid state) has been discovered to bepresent in the form of two pharmaceutically active compounds having themethoxy group on the benzimidazole ring at the 6- and 5-positions.Additionally, Applicants have discovered the presence of a second chirallocation at the pyridine ring plane in each of the two compounds suchthat each compound has two positional isomers and four diastereomers.Therefore, the present invention provides these individual compounds,along with any salts, hydrates, solvates, combinations thereof, andpolymorphs thereof, compositions of the above, and methods of making thesame that are not taught or suggested by the prior art, pharmaceuticalformulations of the compounds, compositions, and complexes of thepresent invention, and methods for using the same.

SUMMARY OF THE INVENTION

[0010] The present invention generally provides compounds represented byformulae (Ia) and (Ib), compositions of compounds represented byformulae (Ia) and (Ib) which typically are co crystallized in part or inwhole, one or more pharmaceutically acceptable salts, solvates,hydrates, or combinations of such compounds and compositions, andcomplexes thereof. Individual diastereomers of the above andcombinations of such diastereomers are also provided. The invention alsoprovides compositions and pharmaceutical formulations of the above.Methods of making the above are also provided by the present invention.

[0011] More specifically, the present discovery pertains to novelcompounds, particularly compounds of the present invention that have amethoxy moiety at the 6-position on the benzimidazole ring, andcompositions comprising compounds having methoxy groups at the 5- and6-positions, respectively. It is unexpected that these individualcompounds are present in the solid state and, furthermore, inco-crystalline form. Ratios of the above isomers can be manipulated, andnovel compounds, encompassing a myriad of ratios of diastereomers ofsuch compounds are also provided. Each of these is described in greaterdetail hereinafter.

[0012] The invention also provides methods of administering suchcompounds, compositions, and complexes of the present invention to amammal in need of treatment, typically for the treatment of gastric acidrelated diseases.

[0013] As used herein, the plural forms of the terms salts, solvates,hydrates, and the like, refer to both two singular and plural, e.g., asingle salt, multiple salts, singular solvate, multiple solvates,singular hydrate, multiple hydrates, and the like, and combinationsthereof, of the term.

[0014] These and other aspects of the invention are set forth in greaterdetail herein.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] The invention is described hereinbelow in greater detail withreference to its preferred embodiments. These embodiments, however, areset forth to illustrate the invention and are not to be construed as alimitation thereof, the invention being defined by the claims.

[0016] In one aspect, the invention relates to a compound represented byformula (Ia) as set forth below. Applicants have unexpectedly discoveredthat this compound, in solid state, has not been taught or suggested bythe prior art. Additionally, it has been unexpectedly discovered thatthis newly-discovered compound has two distinct chiral locations insolid state: (1) a chiral center at the sulfoxide group and (2) a chiralplane located at the pyridinal moiety of such compound. Morespecifically, it has been furthered discovered that when R₄ is alkoxy,or other appropriate substituents, such group is locked into a fixedconfiguration generally perpendicular to the pyridine plane by thesteric hindrance of the two substituents located in the R₃ and R₅positions providing R₃ and R₅ are not hydrogen. The locked orientationof this substituent in solid state, preferably methoxy, gives rise to achiral plane in which part or all of such substituent, preferably themethyl substituent of such preferred methoxy group, is located eitherabove or below the unsymmetrical pyridine chiral plane. However, insolution the R₄ alkoxy substituent of compounds represented by formulaeIa and Ib herein are not necessarily locked in such orientation.

[0017] The compound represented by formula (Ia) is as follows:

[0018] wherein:

[0019] S_(x) represents a chiral sulfur atom comprising at least one ofthe diastereomers represented by S_(xa) and S_(xb), wherein S_(xa) isthe (−) enantiomer and S_(xb) is the (+) enantiomer,

[0020] R is alkoxy;

[0021] R₁ is selected from the group consisting of hydrogen, alkyl,halogen, carboalkoxy, alkoxy, and alkanoyl;

[0022] R₂ is hydrogen or alkyl; and

[0023] R₃, R₄, and R₅ may be the same or different and are each selectedfrom the group consisting of hydrogen, alkyl, alkoxy, and alkoxyalkoxy,

[0024] wherein when R₄ is alkoxy and neither R₃ nor R₅ are hydrogen, thealkyl substituent of such alkoxy group is selected from the groupconsisting of at least one of the enantiomers represented by R_(4q) andR_(4z) wherein R_(4q) is the (−) enantiomer and lies above the chiralplane; and R_(4z) is the (+) enantiomer and lies below the chiral plane;

[0025] or one or more pharmaceutically acceptable salts, solvates,hydrates, or combinations thereof of said compound(s) represented byformula (Ia).

[0026] In one embodiment, all of R₃, R₄, and R₅ are not hydrogen. Inanother embodiment, when two of R₃, R₄, and R₅ are hydrogen, the thirdis not methyl. The compound represented by formula (Ia) is preferablypresent in solid state.

[0027] The term “alkoxy” preferably refers to alkoxy groups having up to5 carbon atoms more, preferably up to 3 carbon atoms such as, forexample, methoxy, ethoxy, n-propoxy, or isopropoxy.

[0028] The term “carboalkoxy” preferably refers to carboalkoxy groupshaving up to 5 carbon atoms such as, for example, carbomethoxy,carboethoxy, carbopropoxy, and carbobutoxy.

[0029] The term “alkoxyalkoxy” preferably refers to alkoxyalkoxy groupshaving up to 5 carbon atoms such as, for example, methoxymethoxy,ethoxyethoxy, and the like. Methoxyethoxy and the like is alsoencompassed under this definition.

[0030] The term “alkyl” preferably refers to alkyl groups having up to 7carbon atoms, more preferably up to 4 carbon atoms, and is thuspreferably selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, orisobutyl.

[0031] The term “halogen” refers to chloro, bromo, fluoro, or iodo.

[0032] The term “alkanoyl” preferably refers to alkanoyl groups havingup to 4 carbon atoms. Examples include formyl, acetyl, and propionyl.

[0033] In a preferred embodiment, R is methoxy; R₁ is hydrogen; R₂ ishydrogen; R₃ is methyl; R₄ is methoxy; and R₅ is methyl.

[0034] Applicants note that throughout the provisional application uponwhich priority is claimed, the R₁ substituent was referred to as beingin the 4-position in the compound represented by formula (Ia). For thepurposes of the present application, the benzimidazole ring is numberedsuch that the R₁ substituent of the compound of formula (Ia) is presentin the 6-position. The purpose of this change in numbering is to betterconform to generally accepted chemical nomenclature and has no bearingon the location of substituents of compounds described in theprovisional application or herein.

[0035] In various embodiments of the present invention, the compoundsrepresented by formula (Ia) may be present in the form of variousindividual diastereomers including, for example:

[0036] (a) S_(xa)—R_(4q);

[0037] (b) S_(xa)—R_(4z);

[0038] (c) S_(xb)—R_(4q); and

[0039] (d) S_(xb)—R_(4z),

[0040] or pharmaceutically acceptable salts, solvates, hydrates, orcombinations thereof. These descriptions are provided to permitdifferentiation of the various stereoisomers (diastereomers) throughoutthis document, and represent the following in standard chemicalnomenclature:

[0041] (a) S_(xa)—R_(4q), (S)—(S), or (−)-(−);

[0042] (b) S_(xa)—R_(4z), (S)—(R), or (−)-(+);

[0043] (c) S_(xb)—R_(4q), (R)—(S), or (+)-(−); and

[0044] (d) S_(xb)—R_(4z), (R)—(R), or (+)-(+).

[0045] For the purposes of the present invention, the term “enantiomer”refers to diastereomer pairs that are non-superimposable mirror imagesof each other. The term “enantiomeric pair” as referenced herein refersto pairs of enantiomers that generate a racemic mixture. Examples ofenantiomeric pairs include: (1) S—S and R—R and (2) S—R and R—S of thecompounds of formulae (Ia) and/or (Ib). The term “(−) enantiomer” mayencompass any of the diastereomers S—S or S—R and pairs thereof. Theterm “(+) enantiomer” may encompass any of the diastereomers R—R and R—Sand pairs thereof.

[0046] Preferred embodiments of various species of the compoundrepresented

[0047] by formula (Ia) are represented by the formulae (Iai), (Iaii),(Iaiii), and (Iaiv):

[0048] wherein S_(x) is S_(xa), or one or more pharmaceuticallyacceptable salts, solvates, hydrates, or combinations thereof of saidcompound represented by formula (Iai);

[0049] wherein S_(x) is S_(xa), or one or more pharmaceuticallyacceptable salts, solvates, hydrates, or combinations thereof of saidcompound represented by formula (Iaii);

[0050] wherein S_(x) is S_(xb), or one or more pharmaceuticallyacceptable salts, solvates, hydrates, or combinations thereof of saidcompound represented by formula (Iaiii); and

[0051] wherein S_(x) is S_(xb), or one or more pharmaceuticallyacceptable salts, solvates, hydrates, or combinations thereof of saidcompound represented by formula (Iaiv).

[0052] The above compounds may be made by various methods includingthose set forth in greater detail herein. Other methods may be also beemployed.

[0053] In another aspect, the invention relates to a compositioncomprising two or more compounds represent by the formula (Ia) set forthherein. In particular, and as discussed in greater detail herein,Applicants provide any combination of any of the four diastereomers invarying ratio amounts.

[0054] wherein:

[0055] S_(x) represents a chiral sulfur atom comprising at least one ofthe enantiomers represented by S_(xa) and S_(xb), wherein S_(xa) is the(−) enantiomer and S_(xb) is the (+) enantiomer,

[0056] R is alkoxy;

[0057] R₁ is selected from the group consisting of hydrogen, alkyl,halogen, carboalkoxy, alkoxy, and alkanoyl;

[0058] R₂ is hydrogen or alkyl; and

[0059] R₃, R₄, and R₅ may be the same or different and are each selectedfrom the group consisting of hydrogen, alkyl, alkoxy, and alkoxyalkoxy,.wherein when R₄ is alkoxy and neither R₃ nor R₅ are hydrogen, the alkylsubstituent of such alkoxy group is selected from the group consistingof at least one of the enantiomers represented by R_(4q) and R_(4z),wherein R_(4q) is the (−) enantiomer and lies above the chiral plane;and R_(4z) is the (+) enantiomer. and lies below the chiral plane;.

[0060] or one or more pharmaceutically acceptable salts, solvates,hydrates, or combinations thereof of said compounds represented byformula (Ia).

[0061] The compositions of two or more compounds may contain variousamounts of the enantiomers S_(xa), S_(xb), R_(4q), and R_(4z). Methodsfor making the various enantiomers and diastereomers are set forthherein. In one embodiment, for example, each of the diastereomersrepresented by S_(xa) and S_(xb), in the compounds represented byformula (Ia) is present in a range from about 0 percent (w/w) to about100 percent (w/w) such that the total percentage of the sum of S_(xa)and S_(xb) equals about 100 percent (w/w). In another embodiment, eachof the enantiomers represented by R_(4q) and R_(4z) is present in arange from about 0 percent (w/w) to about 100 percent (w/w) such thatwhen the total percentage of the sum of R_(4q) and R_(4z) equals about100 percent (w/w).

[0062] In the above composition, each of the at least two compounds maybe the same or different. Any number of combinations of individualdiastereomers or combinations thereof of the compound represented byformula (Ia) may be present in the composition. Examples of suchdiastereomers are as follows: S_(xa)—R_(4q); S_(xa)—R_(4z);S_(xb)—R_(4q); and S_(xb)—R_(4z), or pharmaceutically acceptable salts,solvates, hydrates, or combinations thereof of the compound representedby formula (Ia).

[0063] In various embodiments, the above diastereomers or combinationsthereof may be present in such a manner wherein the composition forms aracemic mixture. In other embodiments, the diastereomers may be presentin such a manner wherein the composition does not form a racemicmixture. In one embodiment, the diastereomers of each of the compoundsrepresented by formula (Ia) in the composition are S_(xa)—R_(4q) andS_(xb)—R₄₇ or pharmaceutically acceptable salts, solvates, hydrates, orcombinations thereof of the compound represented by formula (Ia). Thesediastereomers may be present in amounts such that the composition formsa racemic mixture, or alternatively, these diastereomers may be presentin amounts such that the composition does not form a racemic mixture. Inanother embodiment, the composition comprising S_(xa)—R_(4q) andS_(xb)—R_(4z) or one or more pharmaceutically acceptable salts,solvates, hydrates, or combinations thereof of the compound representedby formula (Ia) may be essentially free of compounds represented byformula (Ia) having diastereomers S_(xa)—R_(4z) and S_(xb)—R_(4q). Whenused in reference to individual diastereomers throughout this document,the term “essentially free” means that a composition comprisingcompounds of the present invention having such specified diastereomersand diastereomer pairs containing not more than about 5 percentconcentration of compounds having non-specified diastereomers and/ordiastereomer pairs. In one embodiment, for example, compounds havingthese diastereomers (S_(xa)—R_(4q) and S_(xb)—R_(4z)) will generallyform compositions in crystalline form that are free or, more typicallyessentially free of compounds having the diastereomers of S_(xa)—R_(4z)and S_(xb)—R_(4q).

[0064] In another embodiment, the diastereomers of each of the compoundsrepresented by formula (Ia) in the composition are S_(xa)—R_(4q) andS_(xa)—R_(4z), or one or more pharmaceutically acceptable salts,solvates, hydrates, or combinations thereof of the compound representedby formula (Ia). In one example of this embodiment, the abovecomposition is essentially free of compounds represented by formula (Ia)having diastereomers represented by S_(xb)—R_(4q) and/or S_(xb)—R_(4z).Typically, this composition is in the form of an oil which, using thetechnique taught hereinafter, may form a crystalline, generally amicrocrystalline, composition. Such a crystalline composition may beformed, typically with significant difficulty, by various techniques,but it is preferred to form a “salt” of such composition which may beformed independently or, preferably, in situ, as described hereinafter.Contrary to teachings in the art, methods typically known to theordinarily skilled artisan may or may not form a salt of compounds andcompositions of the present invention, but may, in fact, form previouslyunknown and unrecognized complexes which are described herein. As usedherein, the term “salt” or “salts”, in addition to its traditionalmeaning in the art, also refers to such complexes, except as otherwiseset forth herein.

[0065] In another embodiment, the diastereomers of each of the compoundsrepresented by formula (Ia) in the composition are S_(xb)—R_(4z) andS_(xb)—R_(4q), or one or more pharmaceutically acceptable salts,solvates, hydrates, or combinations thereof of the compound representedby formula (Ia). In one example of this embodiment, the abovecomposition is essentially free of compounds represented by formula (Ia)having diastereomers represented by S_(xa)—R_(4z) and/or S_(xa)—R_(4q).Otherwise, a salt of such composition may also be formed independentlyor, preferably, in situ, as described hereinafter.

[0066] In another embodiment, the diastereomers of each of the compoundsrepresented by formula (Ia) in the composition is S_(xa)—R_(4q) or oneor more pharmaceutically acceptable salts, solvates, hydrates, orcombinations thereof of the compound represented by formula (Ia). In anexample of this embodiment, the composition is optically pure. The term“optically pure” has the meaning generally accepted in the art, and alsoincludes given or selected diastereomers and/or diastereomer pairs beingessentially free of other compounds and/or impurities that wouldsubstantially affect the optical rotation of the composition. In anotherexample of this embodiment, the composition is essentially free ofcompounds represented by the formula (Ia) having diastereomersS_(xa)—R_(4z), S_(xb)—R_(4q), and S_(xb)—R_(4z).

[0067] In another embodiment, the diastereomers of each of the compoundsrepresented by formula (Ia) in the composition is S_(xa)—R_(4z) or oneore more pharmaceutically acceptable salts, solvates, hydrates, orcombinations thereof of the compound represented by formula (Ia). In oneexample of this embodiment, the composition is optically pure as definedherein. In another example of this embodiment, the composition isessentially free of compounds represented by the formula (Ia) havingdiastereomers S_(xa)—R_(4q), S_(xb)—R_(4q), and S_(xb)—R_(4z).

[0068] In another embodiment, the diastereomers of each of the compoundsrepresented by formula (Ia) in the composition is S_(xb)—R_(4q) or oneor more pharmaceutically acceptable salts, solvates, hydrates, orcombinations thereof of the compound represented by formula (Ia). In anexample of this embodiment, the composition is optically pure aspreferably defined herein. In another example of this embodiment, thecomposition is essentially free of compounds represented by the formula(Ia) having diastereomers S_(xa)—R_(4q), S_(xa)—R_(4z), andS_(xb)—R_(4z).

[0069] In another embodiment, the diastereomers of each of the compoundsrepresented by formula (Ia) in the composition is S_(xb)—R_(4z) or oneor more pharmaceutically acceptable salts, solvates, hydrates, orcombinations thereof of the compound represented by formula (Ia). In anexample of this embodiment, the composition is optically pure. Inanother example of this embodiment, the composition is essentially freeof compounds represented by. the formula (Ia) having diastereomersS_(xa)—R_(4q), S_(xa)—R_(4z) and S_(xb)—R_(4q).

[0070] Compounds of the present invention comprising each of theindividual diastereomers represented by S_(xa)—R_(4q); S_(xa)—R_(4z);S_(xb)—R_(4q); and S_(xb)—R_(4z) may individually provide significantlygreater biological activity for the prevention and/or treatment of thedisease states discussed hereinbelow than compounds of the presentinvention having combinations of such diastereomers.

[0071] Accordingly, methods of the present invention provide forimproved biological activity/efficacy (e.g. inhibition of gastric acidsecretions and, thus, treatment of gastric acid disturbances in mammals,including humans) of pharmaceutically active compounds omeprazole andesomeprazole, as presently known in the art, comprising administering tosuch mammals in need of treatment a non-toxic, therapeutically effectiveamount of any composition of the present invention comprising compoundsor compositions of the present invention having individual diastereomerscomprising S_(xa)—R_(4q); S_(xa)—R_(4z); S_(xb)—R_(4q); orS_(xb)—R_(4z), or one or more pharmaceutically acceptable salts,solvates, hydrates, or combinations thereof. Also provided are suchmethods wherein said compounds or complexes of the present inventionhaving said selected individual diastereomer pair essentially free ofcompounds of the present invention having diastereomer pairs other thansaid selected individual diastereomers. A preferred diastereomer isS_(xa)—R_(4q), and an especially preferred diastereomer isS_(xa)—R_(4z).

[0072] In addition, the present invention also provides for improvedbiological activity/efficacy of compositions of the present inventioncomprising compounds or compositions of the present invention having twoor more diastereomers comprising S_(xa)—R_(4q); S_(xa)—R_(4z);S_(xb)—R_(4q); or S_(xb)—R_(4z), comprising administering to mammals,including humans, in need of inhibition of gastric acid secretion and,thus, treatment of gastric acid disease states, any composition of thepresent invention comprising compounds, compositions, or complexes ofthe present invention having an individual diastereomer selected fromthe group consisting of S_(xa)—R_(4q); S_(xa)—R_(4z); S_(xb)—R_(4q); andS_(xb)—R_(4z), or one or more pharmaceutically acceptable salts,solvates, hydrates, or combinations thereof. Also provided are suchmethods wherein said compounds, compositions, or complexes of thepresent invention having said selected individual diastereomeressentially free of compounds of the present invention havingdiastereomers other than said selected individual diastereomer.

[0073] In any of the above embodiments, each of the two or morecompounds represented by formula (Ia), which each of said compounds maybe the same or different, except as otherwise designated, are preferablycompounds of the formulae represented by (Iai, (Iaii), (Iaiii), or(Iaiv):

[0074] wherein S_(x) is S_(xa), or one or more pharmaceuticallyacceptable salts, solvates, hydrates, or combinations thereof of thecompound represented by formula (Iai);

[0075] wherein S_(x) is S_(xa), or one or more pharmaceuticallyacceptable salts, solvates, hydrates, or combinations thereof of thecompound represented by formula (Iaii);

[0076] wherein S_(x) is S_(xb), or one or more pharmaceuticallyacceptable salts, solvates, hydrates, or combinations thereof of thecompound represented by formula (Iaiii); and

[0077] wherein S_(x) is S_(xb), or one or more pharmaceuticallyacceptable salts, solvates, hydrates, or combinations thereof of thecompound represented by formula (Iaiv). Other species of the compoundrepresented by the formula (Ia) may be employed for the purposes of theinvention.

[0078] Any of the embodiments encompassing the compound(s) representedby formula (Ia), as individual compounds or in compositions and/orcomplexes of the present invention, or one or more pharmaceuticallyacceptable salts, solvates, hydrates, or combinations thereof, aretypically present in crystalline form, in part or in whole.

[0079] In another aspect, the invention also provides compositions ofactive pharmaceutical ingredient (“API”) comprising any of thecompounds, compositions, or complexes of the present invention, each ofwhich may be present in crystalline form, in part or in whole.Advantageously, each such compositions and/or complexes comprisingcompounds represented by formula (Ia) may also include any one or moreof the specific compounds represented by formulae (Iai), (Iaii),(Iaiii), and (Iaiv), or pharmaceutically acceptable salts, solvates,hydrates, polymorphs, or combinations thereof, whether in crystallineform, amorphous form, or a combination thereof. Each can be used as thebases for any such API composition.

[0080] The invention also provides any of the compositions set forthherein comprising the two or more compounds of formula (Ia), that may bethe same or different, being essentially free of compounds representedby formula (Ib):

[0081] wherein:

[0082] S_(x) represents a chiral sulfur atom comprising at least one ofthe enantiomers represented by S_(xa) and S_(xb), wherein S_(xa) is the(−) enantiomer and S_(xb) is the (+) enantiomer,

[0083] R is alkoxy;

[0084] R₁ is selected from the group consisting of hydrogen, alkyl,halogen, carboalkoxy, alkoxy, and alkanoyl;

[0085] R₂ is hydrogen or alkyl; and

[0086] R₃, R₄, and R₅ may be the same or different and are each selectedfrom the group consisting of hydrogen, alkyl, alkoxy, and alkoxyalkoxy,

[0087] wherein when R₄ is alkoxy and neither R₃ nor R₅ are hydrogen, thealkyl substituent of such alkoxy group is selected from the groupconsisting of at least one of the enantiomers represented by R_(4q) andR_(4z); wherein R_(4q) is the (−) enantiomer and lies above the chiralplane; and R_(4z) is the (+) enantiomer and lies below the chiral plane;

[0088] or one or more pharmaceutically acceptable salts, solvates,hydrates, or combinations thereof of said compounds represented byformula (Ib).

[0089] For the purposes of the invention, the term “pure” refers tocompounds of the formula (Ia) being present in an amount such that othercomponents, including compounds represented by formula (Ib), are presentin amounts generally below limits detectable by conventional technology,preferably compounds of formula (Ia) being present in an amount of atleast about 97-98 percent purity (w/w). As used herein, the term“essentially free” of compounds of formula (Ib) refers to thecompound(s) represented by formula (Ia) preferably being present in anamount that is less than about 5 percent (w/w), more preferably about 4percent (w/w) or less, of such compounds represented by formula (Ib) insuch composition.

[0090] In another aspect, and as discussed in greater detail herein,Applicants have discovered that the compounds of formulae (Ia) and (Ib)are typically formed in a manner such that they are present in the samecrystalline lattice (i.e., the compounds co-crystallize, in part or inwhole, from solution). Thus, in this aspect, the invention furtherrelates to compositions comprising a one to one ratio of molecules of.

[0091] (a) a compound represented by formula (Ia):

[0092] wherein:

[0093] S_(x) represents a chiral sulfur atom comprising at least one ofthe enantiomers represented by S_(xa) and S_(xb) wherein S_(xa) is the(−) enantiomer and S_(xb) is the (+) enantiomer:

[0094] R is alkoxy;

[0095] R₁ is selected from the group consisting of hydrogen, alkyl,halogen, carboalkoxy, alkoxy, and alkanoyl;

[0096] R₂ is hydrogen or alkyl; and

[0097] R₃, R₄ and R₅ may be the same or different and are each selectedfrom the group consisting of hydrogen, alkyl, alkoxy, and alkoxyalkoxy,

[0098] wherein when R₄ is alkoxy and neither R₃ nor R₅ are hydrogen, thealkyl substituent of such alkoxy group is selected from the groupconsisting of at least one of the enantiomers represented by R_(4q) andR_(4z) wherein R_(4q) is the (−) enantiomer and lies above the chiralplane; and R_(4z) is the (+) enantiomer and lies below the chiral plane,or one or more pharmaceutically acceptable salts, solvates, hydrates, orcombinations thereof; in combination with, and preferablyco-crystallized with:

[0099] (by a compound represented by formula (Ib):

[0100] wherein:

[0101] S_(x) represents a chiral sulfur atom comprising at least one ofthe enantiomers represented by S_(xa) and S_(xb), wherein S_(xa) is the(−) enantiomer and S_(xb) is the (+) enantiomer;

[0102] R is alkoxy;

[0103] R₁ is selected from the group consisting of hydrogen, alkyl,halogen, carboalkoxy, alkoxy, and alkanoyl;

[0104] R₂ is hydrogen or alkyl; and

[0105] R₃, R₄, and R₅ may be the same or different and are each selectedfrom the group consisting of hydrogen, alkyl, alkoxy, and alkoxyalkoxy,wherein when R₄ is alkoxy and neither R₃ nor R₅ are hydrogen, the alkylsubstituent of such alkoxy group is selected from the group consistingof at least one of the enantiomers represented by R_(4q) and R_(4z)wherein R_(4q) is the (−) enantiomer and lies above the chiral plane;and R_(4z) is the (+) enantiomer and lies below the chiral plane;

[0106] wherein R of a compound represented by formula (Ia) and (Ib) eachis preferably the same alkoxy substituent; and

[0107] each substituent of S_(x), R₁, R₂, R₃, R₄, and R₅ of a compoundrepresented by each of formulae (Ia) and (Ib) are preferably the same;

[0108] or one or more pharmaceutically acceptable salts, solvates,hydrates, or combinations thereof of the composition. The compoundsrepresented by formulae (Ia) and (Ib) may be the same or differentrelative to the pyridine enantiomers, but should be the same forsulfoxide enantiomers.

[0109] Any of the above compositions may include various amounts of thecompounds represented by formulae (Ia) and (Ib). In differentembodiments, for example, the composition may comprise the abovecompounds, which may be the same or different in the following ratiosdenoted by (a), (b), and (c):

[0110] (a) compounds represented by formula (Ia) being present in arange from about 1 percent (w/w) to about 99 percent (w/w) and compoundsrepresented by formula (Ib) being present in a range from about 1percent (w/w) to about 99 percent (w/w) such that the sum of the totalpercentage of such compounds represented by formulae (Ia) and (Ib)equals about 100 percent (w/w). A preferred composition comprisescompounds represented by formula (Ia) that is6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole,which is essentially free of a compound represented by formula (Ib);

[0111] (b) compounds represented by formula (Ia) being present in arange from about 96 percent (w/w) to about 99-100 percent (w/w) andcompounds represented by formula (Ib) being present in a range fromabout 0-1 percent (w/w) to about 4 percent (w/w) such that the sum ofthe total percentage of such compounds represented by formulae (Ia) and(Ib) equals about 100 percent (w/w). A preferred (Ia) compound for thiscomposition also is6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleand a preferred (Ib) compound is5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole;and

[0112] (c) compounds represented by formula (Ia) being present in arange from about 1 percent (w/w) to about 91 percent (w/w) and compoundsrepresented by formula (Ib) being present in a range from about 9percent (w/w) to about 99 percent (w/w) such that the sum of the totalpercentage of such compounds represented by formulae (Ia) and (Ib)equals about 100 percent (w/w). In one preferred composition, compoundsrepresented by (Ib) are present in an amount greater than about 15percent. In another preferred composition, compounds represented byformula (Ib) are present in an amount equal to or greater than about 18percent. In each such compositions, a preferred (Ia) compound is6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleand a preferred (Ib) compound is5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole.

[0113] Each of the above embodiments discussed in (a), (b), and (c)above may include various combinations of diastereomers. Suchdiastereomers are as follows: (a) S_(xa)—R_(4q) (b) S_(xa)—R_(4z), (c)S_(xb)—R_(4q) or (d) S_(xb)—R_(4z), or one or more pharmaceuticallyacceptable salts, solvates, hydrates, or combinations thereof of thecompounds represented by formulae (Ia) and (Ib).

[0114] Any of the above composition embodiments may include, forexample, compounds of the pairs (Iai)-(Ibi), (Iaii)-(Ibii),(Iaiii)-(Ibiii), and (Iaiv)-(Ibiv) as follows:

[0115] wherein each S_(x) is S_(xa);

[0116] or one or more pharmaceutically acceptable salts, solvates,hydrates, or combinations thereof of the composition;

[0117] wherein each S_(x) is S_(xa);

[0118] or one or more pharmaceutically acceptable salts, solvates,hydrates, or combinations thereof of the composition;

[0119] wherein each S_(x) is S_(xb);

[0120] or one or more pharmaceutically acceptable salts, solvates,hydrates, or combinations thereof of the composition; and

[0121] wherein each S_(x) is S_(xb);

[0122] or one or more pharmaceutically acceptable salts, solvates,hydrates, or combinations thereof of the composition.

[0123] Hereinafter, the compounds (Iai), (Iaii), (Iaiii), (Iaiv), (Ibi),(Ibii), (Ibiii), and (Ibiv) are defined by the structures presentedabove.

[0124] In another aspect, the invention provides compositions comprisingtwo or more compounds each of compounds represented by formulae (Ia) and(Ib) as described above or one or more pharmaceutically acceptablesalts, solvates, hydrates, or combinations thereof of the compoundsrepresented by formulae (Ia) and (Ib). In compositions and complexes ofthe present invention, each of the compounds represented by formulae(Ia) and(Ib) may be the same or different

[0125] The above compositions may include various amounts of thecompounds represented by formulae (Ia) and (Ib). In differentembodiments, for example, the composition may comprise the abovecompounds, that may be the same or different, in the following ratiosdenoted by (a), (b), and (c) as set forth above.

[0126] The above compositions comprising compounds represented byformulae (Ia) and (Ib) may advantageously include various percentages ofthese compounds. In one embodiment for example, the percentage ofcompounds represented by formula (Ib) in the composition is less thanabout 40 percent (w/w) and the percentage of compounds of formula (Ia)is such that the sum of the total percentage of such compoundsrepresented by formulae (Ia) and (Ib) is equal to about 100 percent(w/w). In another embodiment, the percentage of compounds represented byformula (Ib) in said compositions is from about 9 percent (w/w) to about50 percent (w/w) and the percentage of compounds of formula (Ia) is suchthat the sum of the total percentage of such compounds represented byformulae (Ia) and (Ib) is equal to about 100 percent (w/w). Preferably,said percentage of compounds represented by formula (Ib) is about 15percent (w/w) to about 50 percent (w/w), and more preferably from about18 percent (w/w) to about 50 percent (w/w).

[0127] Such composition of such two or more compounds may containvarious amounts of the enantiomers S_(xa), S_(xb), R_(4q), and R_(4z).Methods for making the various enantiomers and diastereomers are setforth herein. In one embodiment, for example, each of the enantiomersrepresented by S_(xa) and S_(xb) in the compounds represented by formula(Ia) is present in a range from about 0 percent (w/w) to about 100percent (w/w) such that the total percentage of the sum of S_(xa) andS_(xb) equals about 100 percent (w/w). In another embodiment, each ofthe enantiomers represented by R_(4q) and R_(4z) is present in a rangefrom about 0 percent (w/w) to about 100 percent (w/w) such that when thetotal percentage of the sum of R_(4q) and R_(4z) equals about 100percent (w/w).

[0128] In such compositions, each of the at least two compounds, may bethe same or different. Any number of combinations of individualdiastereomers or combinations thereof of the compound represented byformula (Ia) may be present in the composition. Examples of suchdiastereomers are as follows: S_(xa)—R_(4q); S_(xa)—R_(4z);S_(xb)—R_(4q); and S_(xb)—R_(4z), or one or more pharmaceuticallyacceptable salts, solvates, hydrates, or combinations thereof of thecompound represented in formulae (Ia) and (Ib).

[0129] In various embodiments, the above diastereomers or combinationsthereof may be present in such a manner wherein the composition forms aracemic mixture. In other embodiments, such diastereomers may be presentin such a manner wherein the composition does not form a racemicmixture.

[0130] In another embodiment, the diastereomers of the compoundsrepresented by formulae (Ia) and (Ib) that are present in the abovecompositions may include, for example, the following: (a) S_(xa)—R_(4q)and (b) S_(xb)—R_(4z) or one or more pharmaceutically acceptable salts,solvates, hydrates, or combinations thereof. In one example of thisembodiment, the composition forms a racemic mixture. In another exampleof this embodiment, the composition does not form a racemic mixture. Inanother example of this embodiment, the composition is essentially freefrom compounds having diastereomers represented by S_(xa)—R_(4z) andS_(xb)—R_(4q).

[0131] In another embodiment, the diastereomers of each of the compoundsrepresented by formulae (Ia) and (Ib) in the composition areS_(xa)—R_(4q) and S_(xa)—R_(4z), or one or more pharmaceuticallyacceptable salts, solvates, hydrates or combinations thereof. In oneexample of this embodiment, the above composition is essentially free ofcompounds represented by formulae (Ia) and (Ib) having diastereomersrepresented by S_(xb)—R_(4q) and/or S_(xb)—R_(4z). Typically, thiscomposition is in the form of an oil which, using the technique taughthereinafter, may form a crystalline, preferably a microcrystalline,composition. Otherwise, a salt of such composition may also be formedindependently or, preferably, in situ, as described hereinafter.

[0132] In another embodiment, the diastereomers of the compoundsrepresented by formulae (Ia) and (Ib) which are present in the abovecompositions may include the following: (a) S_(xb)—R_(4q) and (b)S_(xa)—R_(4z), or one or more pharmaceutically acceptable salts,solvates, hydrates, or combinations thereof. In one example of thisembodiment, the enantiomer represented by S_(xa) in each compound ineach composition is present in optically pure form as defined herein. Inanother example of this embodiment, the composition is essentially freefrom compounds having diastereomers represented by S_(xa)—R_(4q) andS_(xb)—R_(4z). The above compositions comprising the variousdiastereomer components may be present in various amounts. In anotherexample or the above embodiments, the percentage of enantiomersrepresented by R_(4z) for either or both of the compounds represented byformulae (Ia) and (Ib) comprises greater than about 5 percent (w/w) andless than about 49 percent (w/w) in the compounds represented byformulae (Ia) and (Ib). such that the sum of the total percentage ofsuch enantiomers represented by R_(4q) and R_(4z) equals about 100percent (w/w). In another example of the above embodiments, thepercentage of enantiomers represented by R_(4z) for either or both ofthe compounds represented by formulae (Ia) and (Ib) comprises greaterthan about 51 percent (w/w) in the compounds represented by formulae(Ia) and (Ib) such that the sum of the total percentage of suchenantiomers represented by R_(4q) and R_(4z) equals about 100 percent(w/w).

[0133] In another embodiment, the diastereomers of the compoundsrepresented by formulae (Ia) and (Ib) that are present in the abovecompositions may include the following: (a) S_(xb)—R_(4q) and (b)S_(xb)—R_(4z), or one or more pharmaceutically acceptable salts,solvates, hydrates, or combinations thereof. In one example of thisembodiment, the enantiomer represented by S_(xb) in each compound ineach composition is present in optically pure form as defined herein. Inanother example of this embodiment, the composition is essentially freefrom compounds having diastereomers represented by S_(xa)—R_(4q) andS_(xa)—R_(4z). The above compositions comprising the variousdiastereomer components may be present in various amounts. In anotherexample of the above embodiments, the percentage of enantiomersrepresented by R_(4z) for either or both of the compounds represented byformulae (Ia) and (Ib) comprises greater than about 5 percent (w/w) andless than about 49 percent (w/w) in the compounds represented byformulae (Ia) and (Ib) such that the sum of the total percentage of suchenantiomers represented by R_(4q) and R_(4z) equals about 100 percent(w/w). In another example of the above embodiments, the percentage ofenantiomers represented by R_(4z) for either or both of the compoundsrepresented by formulae (Ia) and (Ib) comprises greater than about 51percent (w/w) in the compounds represented by formulae (Ia) and (Ib)such that the sum of the total percentage of such enantiomersrepresented by R_(4q) and R_(4z) equals about 100 percent (w/w).

[0134] In another embodiment of the above composition, the diastereomersof each of such compounds represented by formulae (Ia) and (Ib) each isS_(xa)—R_(4q), or one or more pharmaceutically acceptable salts,solvates, hydrates, or combinations thereof. In various embodiments ofthe compositions of the invention, the compounds represented by formulae(Ia) and (Ib) may be present in optically pure form, with the termoptically pure being preferably defined hereinabove. In another exampleof this embodiment, the composition comprising compounds represented byformulae (Ia) and (Ib) are essentially free of such compounds comprisingeach of the diastereomers represented by: (a) S_(xa)—R_(4z); (b)S_(xb)—R_(4q); and (c) S_(xb)—R_(4z).

[0135] In another embodiment of the above composition, the diastereomersof each of such compounds represented by formulae (Ia) and (Ib) each isS_(xa)—R_(4z), or one or more pharmaceutically acceptable salts,solvates, hydrates, or combinations thereof. In various embodiments ofthe compositions of the invention, the compounds represented by formulae(Ia) and (Ib) may be present in optically pure form, with the termoptically pure being preferably defined herein. In another example ofthis embodiment, the composition comprising compounds represented byformulae (Ia) and (Ib) are essentially free of such compounds comprisingeach of the diastereomers represented by: (a) S_(xa)—R_(4q) (b)S_(xb)—R_(4q) and (c) S_(xb)—R_(4z).

[0136] In another embodiment of the above composition, the diastereomersof each of such compounds represented by formulae (Ia) and (Ib) each isS_(xb)—R_(4q), or one or more pharmaceutically acceptable salts,solvates, hydrates, or combinations thereof. In various embodiments ofthe compositions of the invention, the compounds represented by formulae(Ia) and (Ib) may be present in optically pure form, with the termoptically pure being preferably defined herein. In another example ofthis embodiment, the composition comprising compounds represented byformulae (Ia) and (Ib) are essentially free if such compounds comprisingeach of the diastereomers represented by: (a) S_(xa)—R_(4q) (b)S_(xa)—R_(4z) and (c) S_(xb)—R_(4z).

[0137] In another embodiment of the above composition, the diastereomersof each of such compounds represented by formulae (Ia) and (Ib) each isS_(xb)—R_(4z), or one or more pharmaceutically acceptable salts,solvates, hydrates, or combinations thereof. In various embodiments ofthe compositions of the invention, the compounds represented by formulae(Ia) and (Ib) may be present in optically pure form, with the termoptically pure being preferably defined herein. In another example ofthis embodiment, the composition comprising compounds represented byformulae (Ia) and (Ib) are essentially free of such compounds comprisingeach of the diastereomers represented by: (a) S_(xa)—R_(4q) (b)S_(xa)—R_(4z) and (c) S_(xb)R_(4q).

[0138] Any of the composition embodiments may include, for example,compounds of the pairs (Iai)-(Ibi), (Iaii)-(Ibii), (Iaiii)-(Ibiii), and(Iaiv)-(Ibiv) or one or more pharmaceutically acceptable salts,solvates, hydrates, or combinations thereof as previously set forthherein.

[0139] Any of such composition embodiments comprising any of thecompounds represented by formulae (Ia) and (Ib), individual species ofcompounds (Iai)-(Ibi), (Iaii)-(Ibii), (Iaiii)-(Ibiii), and(Iaiv)-(Ibiv), diastereromers thereof, or one or more pharmaceuticallyacceptable salts, solvates, hydrates, or combinations thereof, may bepresent in crystalline form, amorphous form, or combinations thereof.

[0140] The invention also provides compositions of active pharmaceuticalingredient (“API”) comprising any of the above composition embodiments.Advantageously, any of the compositions comprising compounds representedby formulae (Ia) and (Ib) may also comprise any of the specificcompositions represented by formulae (Iai)-(Ibi); (Iaii)-(Ibii);(Iaiii)-(Ibiii); and (Iaiv)-(Ibiv) or one or more pharmaceuticallyacceptable salts, solvates, hydrates, polymorphs, or combinationsthereof, whether in crystalline form, amorphous form, or a combinationthereof, can be used in any such API compositions.

[0141] The compounds represented by formulae (Ia) and (Ib) may beprepared as described in various embodiments. More specifically, themethods describe forming the compounds in solution. The presence ofeither the compounds of formula (Ia) and/or formulae (Ia) and (Ib) insolution causes formation of the corresponding tautomer. Thus, thesemethods essentially describe forming each series of compounds. However,the present invention provides novel compounds of the formulae (Ia) and(Ib) in their respective solid states.

[0142] Compounds of the present invention are prepared by using avariety of synthetic processes. For example, in the crystallization of6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole(one compound represented by formula (Ia)) and5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sufinyl]-1H-benzimidazole(one compound represented by formula (Ib)) from solution, the amount ofcompound represented by formula (Ia) significantly varies by inter aliathe rate of crystallization. Accordingly, slight variations within thesame process as taught in the prior art, such process not beingappropriately controlled or defined as to regulate the amount ofpreviously unknown compound represented by formula (Ia), will result invarious ratios of compounds represented by formula (Ia) to compoundsrepresented by formula (Ib).

[0143] Additionally, when using such processes represented in the priorart, negligible or trace amounts of previously unknown compounds areformed as described herein. For example, in the preparation of suchcomposition as referenced in the immediately preceding paragraph,compounds having the previously unknown diastereomers S_(xa)—R_(4q) andS_(xb)—R_(4z), are formed with varying and inconsistent ratios ofcompounds represented by formulae (Ia) and (Ib). Also formed in tracequantities, and typically in amorphous form, are compounds representedby formulae (Ia) and (Ib) having the previously unknown diastereomersS_(xa)—R_(4q) and S_(xb)—R_(4q).

[0144] Furthermore, when prior art processes are used with the intent offorming “salts” of such composition, the father broad teachings mayresult in salts, but may also result in the formation of novel complexesthat are described herein.

[0145] Accordingly, the processes taught in the prior art for thepreparation of “omeprazole” as well as “esomeprazole” (the intendedS-isomer of “omeprazole”) provide quantities of previously unknown andunrecognized compounds having pharmaceutical activity, or that are usedas intermediates in the preparation of pharmaceutically active compoundsof the present invention, or that are used as prodrugs that convert tothe active metabolite in vivo. Furthermore, many such processes do notinvariably provide the same result when conducted as taught in the priorart

[0146] Embodiments describing methods for preparing the compounds of thepresent invention follow. In various embodiments, neither R₃ nor R₅ arehydrogen when R₄ is alkoxy.

[0147] In one embodiment, the compounds may be formed by oxidizing acompound of formula (II):

[0148] wherein R is alkoxy at the 5- or 6-position, R₁, R₂, R₃, R₄, andR₅ have the meanings defined above, to form the compound of formulae(Ia) or (Ib). The oxidation of the sulfur atom to sulfinyl (S→O)typically takes place in the presence of an oxidizing agent selectedfrom the group consisting of nitric acid, hydrogen peroxide, peracids,peresters, ozone, dinitrogentetraoxide, iodosobenzene,N-halosuccinimide, 1-chlorobenzotriazole, t-butylhypochlorite,diazobicyclo-[2,2,2,]-octane bromine complex, sodium metaperiodate,selenium dioxide, manganese dioxide, chromic acid, cericammoniumnitrate, bromine, chlorine, and sulfuryl chloride. The oxidation usuallytakes place in a solvent wherein the oxidizing agent is present in someexcess in relation to the product to be oxidized.

[0149] In another embodiment, a compound of formula (III):

[0150] wherein R, R₁, and R₂ are defined herein, and M is a metalselected from potassium, sodium, and lithium; may be reacted with acompound of formula (IV):

[0151] wherein R₃, R₄, and R₅ have the same meanings as given above, andZ is a reactive esterified hydroxy group to form compounds of formulae(Ia) and (Ib).

[0152] In another embodiment, a compound of formula (V):

[0153] wherein R and R₁ are defined herein and Z₁ is (═S) or a reactiveesterified hydroxy group, wherein when Z₁ is (═S), Z₂ is H, is reactedwith a compound of formula (VI):

[0154] wherein R₂, R₃, R₄, and R₅ have the same meanings as given above,and Z₂ is a reactive esterified hydroxy group or SH, to form anintermediate of formula (II) above, which then is oxidized to givecompounds of formulae (Ia) and (Ib).

[0155] In another embodiment, a compound of formula (VII):

[0156] wherein R and R₁ are defined above is reacted with a compound offormula (VIII):

[0157] wherein R₁, R₃, R₄, and R₅ are defined above, to form anintermediate of formula (II) above, which then is oxidized to givecompounds of formulae (Ia) and (Ib).

[0158] In the reactions above, Z, Z₁, and Z₂ may be a reactiveesterified hydroxy group which is a hydroxy group esterified withstrong, inorganic or organic acid, preferably a hydrohalogen acid, suchas hydrochloric acid, hydrobromic acid, or hydroiodic acid, as well assulfuric acid or a strong organic sulfonic acid, such as, for example, astrong aromatic acid, e.g., benzenesulfonic acid, 4-bromobenzenesulfonicacid or 4-toluenesulfonic acid. The starting materials are known or may,if they should be new, be obtained according to processes known per se.

[0159] In another embodiment, compounds of formulae (Ia) and (Ib) may beformed by reacting a compound of formula (II):

[0160] wherein R, R₁, R₂, R₃, R₄, and R₅ have the meanings definedabove, with m-chloroperoxybenzoic acid in a methylene chloride solution.The reaction should be carried out at a substantially constant pH. Thereaction product is then extracted with a base (e.g., NaOH) and theaqueous phase is separated from the organic phase. An alkyl formate isadded to the aqueous phase resulting in the crystallization of thecompounds of formulae (Ia) and (Ib).

[0161] The invention also provides methods for producing compositions ofcompounds represented by formulae (Ia) and (Ib). As discussed herein,Applicants have unexpectedly discovered that it is possible to obtainthe compounds of formulae (Ia) and (Ib) in combination and, preferablyco crystallized, in part or in whole, compositions in various amountsrelative to one another according to techniques taught below.

[0162] Applicants have confirmed that solution NMR reveals thetautomerization of the compounds of formulae (Ia) and (Ib). Solution NMRsuggests that the tautomerization reaches an equilibrium atapproximately a 2:1 ratio of compounds represented by formula (Ia) tocompounds represented by formula (Ib). Upon crystallization andisolation, the compounds of formula (Ia) appear to be the moreenergetically favorable isomer and crystallizes first. Thisequilibration/crystallization process allows for the predominantisolation of the solid (e.g., crystalline) isomer of compounds offormula (Ia). Through solution NMR experiments, it is believed that theexchange rate of the amine proton during tautomerization may be pHdependent. For example, with the addition of a small amount of base, theproton exchange rate in the NMR was shown to slow, and two distinctproton NMR peaks were observed for each of the benzimidazole aromaticprotons.

[0163] Methods for forming compositions comprising compounds of formulae(Ia) and (Ib) are described herein with reference to certainembodiments. However, variations from these embodiments may be carriedout without departing from these separation methods described by thepresent invention.

[0164] Applicants have determined that compositions of compounds offormulae (Ia) and/or (Ib) may be formed in relative ratios of thecompounds to one another not suggested by the prior art. In oneembodiment, the method may provide such compound represented by formula(Ia) substantially free from its corresponding isomer (compounds offormula (Ib)). Preferably, compounds represented by formula (Ia) arepresent in an amount ranging from about 96 to about 99 percent (w/w).The method generally includes first providing a solution comprising thetautomers of formulae (Ia) and (Ib) and a solvent. Examples of solventsinclude, but are not limited to, aqueous solvents, preferably basifiedsolvents such as, for example, water and ammonia, or organic solvents.Examples of organic solvents include, but are not limited to, ketones(e.g., acetone), nitrile solvents (e.g., acetonitrile,acetonitrile/water), amine solvents (e.g., dimethyl formamide (DMF) orpyridine), aryl solvents (e.g., toluene), halogenated solvents (e.g.,methylene chloride, chloroform), alcohols (e.g., methanol, ethanol),ammonium hydroxide, and sulfur-containing solvents (e.g., dimethylsulfoxide (DMSO)). Mixtures of the above may also be employed.

[0165] Preferably, the solution is saturated. The solution is evaporatedslowly (preferably from about 3 days to about 7 days) until crystalformation is achieved, with the compounds represented by formulae (Ia)and/or (Ib) typically co-crystallizing in the same lattice.

[0166] Advantageously, the relative amounts of compounds of formulae(Ia) and (Ib) that may be obtained in co-crystalline form can bemanipulated by judicious selection of a number of variables relating to,but not necessarily limited to, solvent choice, humidity, temperature,and vapor diffusion control rate. The selection of solvent for use inthe method may be governed by various considerations. For example,although not intending to be bound by theory, it is believed that theuse of slower evaporation solvents (e.g., DMF) and the solvent's orsolvents' controlled evaporation at lower temperatures produces crystalswith a higher percentage of compounds represented by formula (Ia) in thecrystalline lattice, preferably compounds of formula (Ia) being pure oressentially free of compounds represented by formula (Ib) as definedherein. In other embodiments, organic solvents such as, for example,methylene chloride, ethanol, and chloroform are capable of yieldingcrystals with higher percentages of compounds represented by formula(Ib) in such crystalline lattice, typically up to about 20 percent (w/w)to about 50 percent (w/w) of compounds represented by formula (Ib).

[0167] With all other factors being consistent, it is believed that thepercentage of moisture present in the crystallization chamber isdirectly proportional to the percentage of compounds represented byformula (Ib). Higher levels of humidity in the chamber increase thepercentage of compounds represented by formula (Ib) which crystallizesin the crystalline lattice.

[0168] With all other factors being consistent, temperature does notappear to significantly influence which of the compounds of the presentinvention (e.g., compounds represented by formulae (Ia) and (Ib)) willbe formed, but may influence the size and clarity of such crystals.Typically, temperatures below ambient temperature provides crystalshaving larger size and better clarity.

[0169] The crystallization (e.g., recrystallization) rate may also beinfluenced by the rate of solvent evaporation, and is influenced byusing methods well known in the art. In one embodiment, by exposing asample of compounds represented by formulae (Ia) and (Ib) to thesurrounding environment, the rate of evaporation should increase and theformation of such compounds represented by formula (Ib) in the crystallattice should increase. Conversely, in another embodiment, bycontrolling (i.e., slowing) the rate of evaporation, therecrystallization process should be slowed, thus yielding increasedamounts of such compounds represented by formula (Ia).

[0170] Accordingly, one may manipulate various processing variables asset forth herein to yield the percentage of compound(s) represented byformulae (Ia) and/or (Ib) as desired. For example, in one preferredembodiment, using DMF, reduced evaporation, reduced humidity, andlowered temperatures, higher percentages of the compound represented byformula (Ia) are obtained, preferably from about 96 to about 100 percent(w/w). Crystals containing the higher percentages of the compoundrepresented by formula (Ib) may be produced using a solvent comprisingchloroform or methylene chloride, increased evaporation, and ambienttemperature.

[0171] The structure of one compound of formula (Ia), and in particular,6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole,has been confirmed by x-ray single crystal analyses on isolated crystalsformed in accordance with the above methods.

[0172] By employing the above method(s) of obtaining the compoundrepresented by formula (Ia) in solid state, one obtains the (−) and (+)enantiomers as a racemic mixture, with these enantiomers includingvarious amounts of diastereomers as set forth herein. In one embodiment,Applicants have discovered that the (−) and (+) enantiomers may bepredominantly present as the S_(xa)—R_(4q) and S_(xb)—R_(4z)diastereomers respectively. Although not intending to be bound bytheory, in this embodiment, the two molecules (i.e., compounds offormulae (Ia) and (Ib)) co-crystallize in a centric space group in whichthe molecules are related to each other through a center of inversionand linked by hydrogen bonding from the amine hydrogens to the sulfoxideoxygens. The R₄ methoxy methyl is directed towards the center of thebridged complex. Examination of the contact distances in the regionwhere the other methoxy methyl would presumably reside demonstrates thatthere is not adequate space within the lattice for the otherdiastereomers (S_(xa)—R_(4z) and S_(xb)—R_(4q)) to coexist. In thisembodiment, the compound represented by formula (Ia) may comprise about99 percent (w/w) of the S_(xb)—R_(4z) and S_(xa)—R_(4q) diastereomersand the remaining percentage of other components which may include, forexample, the diastereomers S_(xa)—R₄. and S_(xb)—R_(4q), generally inamorphous form.

[0173] In the above embodiment, the crystallization of the compoundsrepresented by formulae (Ia) and (Ib) is believed to be controlledthermodynamically by a bipyrimidal inversion equilibrium at thesulfoxide chiral center which forces the S_(xb)—R_(4q) diastereomer toS_(xa)—R_(4q) and the S_(xa)—R_(4z) diastereomer to S_(xb)—R_(4z)diastereomers. Such behavior may be confirmed by examining the x-raycrystal structure, and more specifically, the crystal packing. Notintending to be bound by theory, it is believed that the molecular.packing does not provide adequate area for the other diastereomers to bepresent within the current crystal lattice.

[0174] Upon obtaining a composition comprising a compound of formula(Ia) as described above, one may apply a suitable technique to resolvethe individual (−) and (+) enantiomers. One may then apply a suitabletechnique (including, for example, those described subsequently) toresolve the diastereomer components in the (−) and (+) enantiomers. Withrespect to the (−) enantiomer of such compound represented by formula(Ia), in a number of embodiments, the above techniques are capable ofyielding about 95 percent (w/w) of the S_(xa)—R_(4q) diastereomer andabout 5 percent (w/w) of the S_(xa)—R_(4z) diastereomer of the compoundof formula (Ia), particularly in the specific embodiment in whichcompound (Ia) is described by compounds of the formulae (Iai) and(Iaii). Although not intending to be bound by theory, it is believedthat the bipyramidal inversion equilibrium at the sulfoxide chiralcenter forces the S_(xb)—R_(4q) diastereomer to the S_(xa)—R_(4q)diastereomer of such compound represented by formula (Ia). Moreover, thecomposition of the resolved (+) enantiomer by the resolution techniquesset forth herein allow for the formation of predominantly theS_(xb)—R_(4z) diastereomer (e.g., about 95 percent (w/w)). Similar tothe formation of the S_(xa)—R_(4q) diastereomer, a bipyramidal inversionequilibrium is believed to occur forcing the S_(xa)—R_(4z) diastereomerto the S_(xb)—R_(4z) diastereomer. Alternatively, in another embodiment,a biosynthesis resolution method allows for the (−) enantiomer to beresolved from the (+) enantiomer wherein the composition of the (−)enantiomer includes about 50 percent (w/w) of the S_(xa)—R_(4q)diastereomer and about 50 percent (w/w) of the S_(xa)—R_(4z)diastereomer. Likewise, the (+) diastereomer resolved by thisbiosynthesis method includes about 50 percent (w/w) of the S_(xb)—R_(4q)diastereomer and about 50 percent (w/w) of the S_(xb)—R_(4z).diastereomer.

[0175] The above techniques can also be used to co-crystallize a metalion analogue of the compounds represented by formulae (Ia) and (Ib) inthe amounts set forth above. Redissolving such compound(s) is believedto initiate the bipyramidal inversion which generates the distereomercomponents S_(xa)—R_(4q), S_(xa)—R_(4z), S_(xb)—R_(4q), andS_(xb)—R_(4z) in amounts which are believed to depend upon, but notpotentially limited to, the bipyridimal inversion equilibrium rate, thetime it takes to create the metal analog, and the time it takes tocrystallize the analog. It should be appreciated that these variablesmay be manipulated by one skilled in the art. Preferably, the range ofeach of the four diastereomers can range from about a 60:40 ratio toabout a 100:0 ratio of enantiomeric S_(xa)—R_(4z) and S_(xb)—R_(4z)analogs to S_(xa)—R_(4q) and S_(xb)—R_(4z) analogs.

[0176] The present invention also provides a method of forming compoundsof formula (Ib) in the solid state. In a preferred specific embodiment,the method encompasses increasing the level of the selected compoundrepresented by formula (Ib) in a composition comprising the selectedcompounds represented by formulae (Ia) and (Ib). The method comprisessubjecting such compound of formula (Ia) and/or formulae (Ia) and (Ib)to grinding conditions sufficient to permit a solid state phasetransformation of such compound(s) to a compound of formula (Ib), or, atleast, a composition having an increased percentage of such compoundrepresented by formula (Ib) compared to the starting material.Preferably, the compound represented by the formula (Ia) is present in acomposition and the above method increases the percentage of thecompound represented by formula (Ib) present in the composition. In thisembodiment, prior to the subjecting step, the composition may containthe compound represented by formula (Ia) essentially free from thecompound represented by formula (Ib), although it should be appreciatedthat other examples are contemplated in which the composition comprisesthe compounds of formulae (Ia) and (Ib) in amounts set forth herein.

[0177] Various conditions may be manipulated during the subjecting stepto govern the amount of compound represented by formula (Ib), e.g.,revolutions per minute (RPM) and length of subjecting step. Thesubjecting step is preferably carried out from about 350 rpm to about500 rpm, more preferably from about 350 rpm to about 450 rpm, and mostpreferably about 450 rpm. A preferred time for carrying out thesubjecting step is from about 5 to about 30 minutes, more preferablyfrom about 10 min to about 30 min, and most preferably about 15 minutes.Advantageously, the compounds are not degraded during this operation.The subjecting step may be carried out by various machines that applyappropriate grinding energies to solid materials. Preferably, themachine is a mechanical grinder. One example of a suitable grinder isset forth in U.S. Pat. No. 5,773,173 to Whittle et al., the disclosureof which is incorporated herein by reference in its entirety. It shouldbe appreciated that one may employ embodiments other than thosedescribed above and still be within the scope of the method of formingsuch compounds of the formula (Ib) in solid state.

[0178] Although not intending to be bound by theory, such compounds offormula (Ia) are believed to be crystalline with little amorphouscontent. However, when grinding is applied to a sclid sample comprisingthe compound of formula (Ia), and in a preferred embodiment thecompounds of formulae (Ia) and (Ib), an increase in the amorphouscharacter of the sample is believed to result along with an increase inthe amount of compound of formula (Ib). Again, not intending to be boundby theory, it is believed that the sample undergoes a solid statetransformation and “recrystallizes” or transforms over a relativelyshort period of time from the more amorphous state to a more crystallinestate subsequent to grinding. Nonetheless, it is believed that byperforming multiple grinding steps in sequence, (i.e., grinding followedby relaxation followed by grinding) one may obtain a solid sample thatbecomes more amorphous in character and hence comprises a greater amountof the compound of the formula (Ib) as opposed to a sample that hasexperienced a lesser amount of grinding.

[0179] The above method may provide various amounts of the compound offormula (Ib).

[0180] The structure of the compound of formula (Ib) can be confirmed bysolid state techniques such as, for example, X-ray powder diffractionpatterns, Raman, FTIR, solid state NMR, and thermal analysis, of theground material and the unground material. For example, comparison ofthe two powder patterns showed distinct decreases in intensity,broadening of the peaks, and an increase in the amorphous nature for theground material. The ground material showed a powder pattern that ismore consistent with the proposed more amorphous nature of the compoundof formula (Ib), e.g.,5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole.

[0181] The present invention also provides the compounds of formulae(Ia) and (Ib) in the form of pharmaceutically acceptable salts asdescribed hereinbelow. Similar to the making of the compounds offormulae (Ia) and/or (Ib) described above, the making of a salt of eachof the compounds of formulae (Ia) and/or (Ib) in solution results in themaking of salts of both compounds due to tautomerization occurring insolution. Thus, these methods describe making salts of both families ofcompounds.

[0182] Depending upon the process conditions and the starting materials,the end product of the synthetic processes for preparing compoundsrepresented by formulae (Ia) and/or (Ib) is typically obtained as a freebase. Basic, neutral or mixed salts may be obtained as well as solvatesand hemi-, mono-, sesqui-, tetra, or polyhydrates. Examples of suitablebases for salt formation include, but is not limited to, compoundscontaining alkali metals or alkali earth metals, although it isappreciated by the skilled artisan that bases containing other types ofmetals may be used. Examples of inorganic bases include, but are notlimited to, sodium hydroxide, sodium carbonate, sodium bicarbonate,potassium hydroxide, calcium hydroxide, magnesium hydroxide, and thelike. Organic bases in the form of, for example, nitrogen-containingcomponents may be also used. Exemplary nitrogen-containing compoundsinclude, but are not limited to, ammonium, organic amines, and the like.The free bases that are obtained may form salts with organic orinorganic acids.

[0183] As discussed in greater detail herein, metal hydrides,particularly sodium hydride, are preferably used in making the salts ofthe compounds of the present invention. Other methods that have beenconventionally thought to be useful in making salts of such compoundshave been found by Applicants to not invariably result in the formationof such salts, but instead have resulted in complex formation. Thus, themethod of making such salts employing the metal hydrides of thesecompounds is not suggested by the prior art

[0184] Acid addition salts may be difficult to form because of the acidlabile nature of the compounds of the invention, but could be formed ata pH above 6.0 since the stability of the compounds increases. Acidssuitable for making such salts may include, but are not limited to,hydrohalogen acids, sulfonic, phosphoric, nitric, and perchloric acids;aliphatic, alicyclic, aromatic, heterocyclic carboxy or sulfonic acids,such as formic, acetic, propionic, succinic, glycolic, lactic, malic,tartaric, citric, ascorbic, maleic, hydroxymaleic, pyruvic,phenylacetic, benzoic, p-aminobenzoic, antranilic, p-hydroxybenzoic,salicylic or p-aminosalicylic acid, embonic, methanesulfonic,ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic,halogenbenzenesulfonic, toluenesulfonic, naphtylsulfonic or sulfanilicacids; methionine, tryptophane, lysine or arginine.

[0185] These or other salts of the new compounds, as e.g., picrates, mayserve as purifying agents of the free bases obtained. Salts of the basesmay be formed, separated from solution, and then the free base may berecovered from a new salt solution in a purer state. Because of therelationship between the new compounds in free base form and theirsalts, it will be understood that the corresponding salts are includedwithin the scope of the invention.

[0186] The salts may be prepared by various techniques. For example,such salts can be prepared from organic compounds when that compound hasan “acidic” proton. The proton may be removed, for example, by a type ofbase that allows for the formation of an anionic species of the compoundcountered by the cation. In embodiments encompassing polar, proticenvironments, such as an alkali or alkaline metal hydroxide or alkalinemetal alkoxide present in an alcohol or mixed organic solvent such as a2-butanone/toluene mixture, it is believed that the conversion to thesalt may be governed by pKa differences. In various embodiments, suchtechniques are capable of yielding salts of the compounds of the presentinvention having the diastereomers represented by S_(xa)—R_(4z) andS_(xb)—R_(4q) in a range from about 60 to about 70 percent (w/w).

[0187] Another example of a method for preparing salts of compoundsrepresented by formulae (Ia) and/or (Ib) comprises subjecting suchcompounds to a polar, aprotic environment to form such salts. Examplesof polar, aprotic environments include, for example, an alkali oralkaline metal hydride in an organic solvent (e.g., tetrahydrofuran(THF) or dimethylformamide (DMF)). Although not intending to be bound bytheory, in polar, aprotic environments, the salt conversion may begoverned by factors such as solubility of both the organic compound andthe base used and the steric hindrance interactions. Although both typesof reactions (e.g., polar, protic environments and polar, aproticenvironments) can be used in forming the salts, reactions taking placein polar, aprotic environments are preferred. For example, using apolar, aprotic environment may preferably provide from about 90 to about95 percent (w/w) yield of salts of the compounds, and/or compositions ofthe present invention. Although various alkali and alkaline metal saltscan be made using the above methods, it is preferred to form sodium ormagnesium salts of compounds of the present invention.

[0188] Typically, a solution of filtered alkali or alkaline metalhydride having a preferred concentration of about 50% to about 70% inmineral oil, preferably sodium or magnesium hydride, is added,preferably in situ, to a solution of one or more selected compoundsand/or compositions of the present invention in an appropriate solventand stirred for about 5 to about 30 minutes. The resulting solution isfiltered, if necessary, and the resulting solids are dried in vacuo,typically at ambient temperature. The resulting powder can bere-crystallized as set forth herein or as known by one of ordinary skillin the chemical arts.

[0189] Alternatively, the desired, previously isolated compounds and/orcompositions of the present invention are added to a solution offiltered alkali or alkaline metal hydride having a preferredconcentration of about 50% to about 70% in mineral oil, preferablysodium or magnesium hydride, stirred, typically for about 5 to about 15minutes, and allowed to sit at ambient temperature. Crystalline salts ofthe present invention result Each of the processes using hydrides forpreparation of salts of compounds and compositions of the presentinvention can result in significantly increased/improved yields comparedto the processes typically used and/or known to the ordinary skilledartisan.

[0190] In addition, other salts may be formed by various reactions. Forexample, in one embodiment, a complex may be formed by reacting thecompounds represented by formulae (Ia) and/or (Ib) with a cationA^(z+)by a suitable technique, e.g., ion-pair extraction. In the aboveembodiment, A is lithium, sodium, potassium, magnesium, calcium,titanium(4+), N⁺(R¹)₄, or:

[0191] wherein R¹ is an alkyl group containing 1 to 4 carbon atoms, andz is 1, 2, or 4.

[0192] For example, tetrabutylammonium salts of the invention may beprepared by dissolving the A^(z+) salt in water containing one or moretetrabutylammonium compounds such as, for example, the chloride orhydroxide followed by extraction of the tetrabutylammonium salt into amethylene chloride phase, and subsequent isolation of thetetrabutylammonium salt. In this manner, other tetraalkylammonium saltsmay be prepared.

[0193] In one embodiment, the salt of the compound of formula (I′) maybe formed by reacting the compound of formulae (Ia) and/or (Ib) with abase capable of releasing the cation A^(z+) wherein z is 1, 2, or 4; andA is lithium, sodium, potassium, magnesium, calcium, titanium(4+),N⁺(R¹)₄, or:

[0194] wherein R¹ is an alkyl group containing 1 to 4 carbon atoms, toprovide a salt of the formula (I′):

[0195] wherein R is alkoxy in the 5- or 6-position: R₁ is selected fromthe group consisting of hydrogen, alkyl, halogen, carboalkoxy, alkoxy,and alkanoyl; R₂ is hydrogen or alkyl; and R₃, R₄, and R₅ may be thesame or different and are each selected from the group consisting ofhydrogen, alkyl, alkoxy, and alkoxyalkoxy, and wherein z and A^(z+) aredefined above.

[0196] In one example, lithium, potassium, or sodium salts of theformula (I′) may be prepared by treating the compounds of the formulae(Ia) and/or (Ib) with LiOH, NaOH, or KOH in an aqueous or nonaqueousmedium, or with LiOR¹, LiNH₂, LiNR¹ ₂, NaOR¹, NaNH₂, NaNR¹ ₂, KOR¹,KNH₂, KNR¹ ₂ wherein R¹ is defined above, in an aqueous or a nonaqueousmedium. Magnesium, calcium, or titanium salts may be prepared bytreating a compound of the formulae (Ia) or (Ib) with Mg(OR¹)₂,Ca(OR¹)₂, CaH₂, Ti(OR¹)₄ or TiH₄, wherein R¹ is defined herein, in anonaqueous solvent such as an alcohol (for the alcoholates), or in anether such as tetrahydrofuran.

[0197] In another example, a salt of the compound of formula (I′)wherein A is:

[0198] may be prepared by treating compounds of the present inventionwith a strong base of the formula:

[0199] dissolved in a solvent such as, for example, an alcohol.

[0200] A salt represented by formula (I′) may be converted to anothersalt of the same formula by exchanging the cation. When both thestarting material and the salt obtained as final product aresufficiently soluble, such an exchange may be performed by using acation-exchange resin saturated with the cation desired in the product.The exchange may also be performed by utilizing the low solubility of adesired salt

[0201] The reaction between the compound of formulae (Ia) and/or (Ib)and A^(z+) may also be carried out by ion-pair extraction. For example,tetrabutylammonium salts of the invention may be prepared by dissolvingthe Na⁺ salt in water containing one or more tetrabutylammoniumcompounds followed by extraction of the tetrabutylammonium salt into amethylene chloride phase, and subsequent isolation of thetetrabutylammonium salt. In this manner, other tetraalkylammonium saltsmay be prepared.

[0202] Illustrative examples of the radical R¹ are methyl, ethyl,n-propyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0203] A preferred method for forming magnesium salts of compounds ofthe present invention is characterized by the following consecutivesteps: a) treating at least one compound of formulae (Ia) and/or (Ib) orsalts thereof with magnesium alcoholate in a solution; b) separatinginorganic salts from the reaction mixture; c) crystallizing themagnesium salts of such formulae (Ia) and/or (Ib); d) isolating theobtained crystalline magnesium salts and, optionally, e) purifying anddrying the crystalline magnesium salts using conventional methods.

[0204] A process for manufacturing the magnesium salts is described asfollows: a lower alcohol, such as methanol, ethanol, n-propanol oriso-propanol, preferably methanol, is treated in a solution of polarsolvents with a weighed amount of magnesium at temperatures betweenabout 0° C. and reflux temperature. The temperature should preferably bebetween about 10° C. and about 40° C. After addition of the magnesium tothe solution the temperature can, in a second step, be raised further tobetween about 0° C. and reflux temperature, preferably about 20° C. toabout 50° C. After termination of the reaction, the temperature isreduced to about 0° C. to about 40° C., preferably about 1° C. to about25° C. The compound of formulae (Ia) and/or (Ib), or a salt thereof, isthen added to the solution and after termination of the reaction themixture is cooled to about −10° C. to about +20° C., preferably about−5° C. to about +5° C. The solvent is then evaporated to about 40 toabout 60 percent of the initial volume, which makes the inorganic saltsprecipitate. The precipitate is separated from the reaction solution,for example, by centrifugation or filtration, and the solution is heatedfrom about 5° C. to about 30° C., whereafter the solution is seeded withmagnesium crystals of the compound of formulae (Ia) and/or (Ib). Anamount of water, which is approximately equal to the volume of thesolution, is added to start the crystallization. The solution is cooledto about −10° C. to about +20° C., preferably about 0° C. to about 10°C., to complete the crystallization. The crystals are then separatedfrom the mother liquor for example, by centrifugation or filtration, andwashed with polar solvents, preferably an aqueous lower alcohol, such asaqueous methanol. Finally, the produced crystals are dried, preferablyunder reduced pressure and heating.

[0205] The magnesium salts may include various amounts of the compoundsof the formulae (Ia) and/or (Ib). For example, in one embodiment, amagnesium salt composition may preferably comprise up to about 30percent (w/w) of the compound of formula (Ib), and more preferably up toabout 27 percent (w/w) of the compound of formula (Ib).

[0206] In another aspect, the invention also provides complexes of thecompound represented by the formulae (Ia) and/or (Ib). In particular,the invention provides a composition comprising a complex of: (a) two ormore compounds encompassed by compositions set forth herein comprisingcompounds represented by formulae (Ia) and/or (Ib); and at least oneatom of a metal cation, preferably an alkali or alkaline metal cation.Exemplary metal cations are selected from the Groups IA; IIA, and IIIaof the periodic table although other cations may be employed.Preferably, the composition is present in crystalline form. Sodium andmagnesium each are examples of preferred cations.

[0207] Such competitions of the present invention may employ solvent(s)that are typically employed in forming complexes. In a preferredembodiment, such compositions further include two solvents. The solventsare those which are capable of donating a pair of electrons, including,for example, alcohols, THF, DMF, DMSO, and mixtures thereof. Thecomplexes of the invention may be formed by using materials which areknown to be used in forming complexes, e.g., alkoxides and hydroxides ofmetal cations such as, without limitation, those described above. Thetwo or more compounds represented by formulae (Ia) and/or (Ib) may bethe same or different and may be present as compounds with any one ofthe four diastereomer configurations (e.g., S_(xa)—R_(4q),S_(xa)—R_(4z), S_(xb)—R_(4q), and S_(xb)—R_(4z)).

[0208] In general, complexes of compounds of formulae (Ia) and/or (Ib)typically include two compounds having at least one metal cationpositioned therein. The metal cation bonds with various appropriate lonepair or electron donating sites on the two compounds, namely oxygen andnitrogen atoms with respect to such compounds. In various preferredembodiments, such complexes also typically include at least one “solventresidue” which is obtained from one or more solvents set forth herein.In such complexes, the solvent residue is bound to the metal cation andthe nitrogen present on the benzimidazole portion of the compounds.Examples of suitable solvent residues include, without limitation,alkoxides (e.g., lower (C₁ to C₄) alkoxides) with ethoxide beingpreferred.

[0209] The ratio of metal cation to compound in a complex of theinvention typically depends on the specific structure of the compoundand the valence of the metal cation. In embodiments employing a solventresidue, the amount of such residue that is employed will typicallydepend on the above factors as well as the type of residue used. Inpreferred embodiments, the ratio of: (1) compounds of formulae (Ia)and/or (Ib) as defined by any of compounds (Iai), (Iaii), (Iaiii),(Iaiv), (Ibi), (Ibii), (Ibii); and (Ibiv), respectively, or combinationsthereof; to (2) one or more metal cation; to (3) solvent residue willtypically be 2:1:4 or 2:2:2 for magnesium or sodium, respectively, andcan otherwise vary depending upon the metal cation and compound used,and the crystalline packing forces respective thereto. Other ratios maybe required depending on the charge of the cation and the type ofcomplex embodiment

[0210] In various embodiments, the compositions comprising the complexesmay be essentially free from compounds represented by formula (Ib), asdefined herein.

[0211] In these embodiments, the term “essentially free” preferablyrefers to such complexes formed with sodium as the metal cationcomprising at least about 95 percent (w/w) of the compound representedby formula (Ia).

[0212] The compositions comprising the complexes described abovepreferably are in crystalline form.

[0213] In certain embodiments, the compositions comprising the complexesmay employ the diastereomers of the compounds represented by formula(Ia) and, if applicable, the compounds represented by formula (Ib)according to any of the embodiments set forth hereinabove. In onenon-limiting embodiment, for example, the concentration of compoundshaving the combination of the diastereomers S_(xa)—R_(4z) andS_(xb)—R_(4q) is from about 50 percent (w/w) to about 100 percent (w/w)of the composition, and the concentration of the compounds having thediastereomers S_(xa)—R_(4q) and S_(xb)—R_(4z) is from about 0 percent(w/w) to about 50 percent (w/w) of the composition, such that the sum ofthe total concentration of all such compounds is about 100 percent(w/w). Preferably, the concentration of such compounds having thecombination of diastereomer pairs S_(xa)—R_(4z) and S_(xa)—R_(4q) isgreater than about 70 percent

[0214] Hydrates and solvates of the compounds of formulae (Ia) and (Ib)along with polymorphs thereof are also provided by the invention and maybe formed according to techniques known to one having ordinary skill inthe pharmaceutical arts. As an example, solvates of any embodimentsencompassing the compounds represented by formula (Ia) may be madeaccording to known techniques. Suitable solvents for use in providingthe solvates are known in the art and may vary according to theparticular embodiment. Exemplary solvents include alcohols, such as,without limitation, methanol, ethanol, and the like.

[0215] The invention also pertains to methods for providing each of thediastereomers S_(xa)—R_(4q), S_(xa)—R_(4z), S_(xb)—R_(4q), andS_(xa)—R_(4z) of the compounds of formulae (Ia) and/or (Ib), or pairsthereof, in resolved form. Preferably, in various embodiments, eachdiastereomer pair of compounds (Ia) and/or (Ib) are essentially free ofthe three other diastereomers, or combinations thereof, e.g., at least95 percent (w/w).

[0216] As set forth herein, the compounds of (Ia) and (Ib) have beendiscovered to exhibit chirality at two distinct locations: (1) an atomicchiral center located at each sulfoxide group (as referenced by thefirst letter denoted in the diastereomer pair designation) and (2) astructural chiral center (i.e., a chiral plane) located at eachpyridinal moiety on the compound (as referenced by the second letterdenoted in the diastereomer pair designation). A preferred method forresolving each of the above diastereomer pairs involves first resolvingthe structural chiral center of the various materials used in makingcompounds (Ia) and/or (Ib) including those set forth herein. Forexample, the starting pyridine compound may be resolved at the R₄position referred to herein, or alternatively one of thepyridinal-moiety containing intermediates can be resolved at the R₄position such as, for example, a thiol compound represented by formulae(II) or (VIII). In this instance, the resolution of the thiol compoundis carried out prior to oxidation which eventually forms compounds offormulae (Ia) and/or (Ib). The actual techniques for resolving thestructural chiral centers may be carried out by various suitablemethods.

[0217] Subsequent to oxidation, the materials used in making thecompounds (Ia) and/or (Ib) are then be resolved at the atomic chiralcenter eventually providing each of the resolved diastereomer pairs ofcompounds (Ia) and/or (Ib). Any number of techniques may be used toresolve the atomic chiral center of these compounds, e.g.,recrystallization from an optically active solvent, use ofmicroorganisms, reactions with optically active acids forming saltswhich can be separated based on different solubilities of thediastereomers. Suitable optically active acids are, for example, the L-and D-forms of tartaric acid, ditolyl-tartaric acid, malic acid,mandelic acid, camphorsulfonic acid or quinic acid.

[0218] In one embodiment, atomic chiral center resolution of thecompounds of formulae (Ia) and (Ib) may be obtained by chromatographictechniques. Materials that may be used in this method include acellulose (e.g., triphenylcarbamoyl-cellulose) coated on a column thatincludes a silica-containing material (e.g., silica or 3-aminopropylsilica). The column may be prepared by suspension in an organic solvent(e.g., methanol or 2-propanol) using an appropriate technique such as,for example, a descending slurry-packing technique.

[0219] Mobile phases for use in this procedure can be prepared byvarious methods, such as, for example, using n-hexane and diethylaminein different ratios. Other materials, however, may be employed such as,without limitation, alcohols (e.g., methanol, ethanol. The compounds offormulae (Ia) and/or (Ib) may be combined in the mobile phase along withother components known in the art such as, for example, a suitablebuffer (e.g., a phosphate compound). The mobile phase is then passedthrough the column under processing (e.g., temperature, flow, andpressure) conditions that may be set by the operator. The diastereomerthat first eluted from the column can be isolated by evaporation of thesolvents. The diastereomer can be deemed isolated by known analyticaltechniques.

[0220] In another embodiment, the formation of compounds of formulae(Ia) and/or (Ib) having resolved atomic chiral centers may be formed bycarrying out the asymmetric oxidation in an organic solvent of apro-chiral sulphide according to the formula (X):

[0221] wherein R, R₁, R₂, R₃, R₄, and R₅ are defined above with R beingpresent in the 6- or 5-position, with an oxidizing agent and a chiraltitanium complex, optionally in the presence of a base.

[0222] A number of oxidizing agents may be employed such as, forexample, a hydroperoxide, more particularly tert-butylhydroperoxide orcumene hydroperoxide.

[0223] The titanium complex suitable for use in the reaction may beprepared using various methods. In one embodiment, the titanium complexis prepared from a chiral ligand and a titanium (IV) compound such as,for example, preferably titanium(IV) alkoxide, and optionally in thepresence of water. An especially preferred titanium (IV) alkoxide istitanium (IV) isoperoxide or isopropoxide. Various amounts of chiraltitanium complex may be used. Typically, an amount less thanapproximately about 0.5 equivalents is preferred and an especiallypreferred amount is about 0.05 to about 0.30 equivalents.

[0224] The titanium complex may also be prepared by reacting titaniumtetrachloride with a chiral ligand in the presence of a base. The chiralligand used in the preparation of the titanium complex is typically abranched or unbranched alkyl diol, or an aromatic diol. Preferred chiraldiols are, for example, esters of tartaric acid, especially (+)-diethylL-tartrate or (−)-diethyl D-tartrate. It should be noted that thetitanium complex may be prepared in the presence of the compound offormula (X) or before the compound of formula (X) is added to thereaction vessel.

[0225] The oxidation is preferably carried out in the presence of abase. For example, the base may be an inorganic or organic base, suchas, but not limited to, a hydrogen carbonate, an amide, or an amine suchas guanidine or an amidine. Examples of other bases includetriethylamine or N,N-diisopropylethylamine.

[0226] The oxidation is typically carried out in the presence of anorganic solvent. The solvent can be selected with respect to suitableconditions. Suitable organic solvents include, but are not limited to,toluene, ethyl acetate, methyl ethyl ketone, methyl isobutyl ketone,diethyl carbonate, tert butyl methyl ether, tetra hydrofuran, methylenechloride, and the like, and blends and mixtures thereof.

[0227] The oxidation is preferably carried out in the organic solvent atambient temperature or just above ambient temperature, e.g., betweenabout 20° C. and about 40° C. It is believed that the reaction times maybe longer if the reaction is carried out below 20° C. The temperature ofthe reaction may be varied according to the intentions of one skilled inthe art.

[0228] The products formed during the oxidation reaction may beextracted with an aqueous solution of ammonia or another N-containingbase to avoid precipitation and/or formation of insoluble titaniumsalts. The aqueous phase is separated from the organic phase of theobtained mixture and the isolated aqueous phase is neutralized by theaddition of a neutralizing agent resulting in the protonation of thediastereomers. The diastereomers may be extracted by an organic solvent.They may also be crystallized in an organic or aqueous solvent resultingin the desired resolved diastereomers of compounds (Ia) and/or (Ib).

[0229] In addition to using the above techniques to provide individualdiastereomers S_(xa)—R_(4q), S_(xa)—R_(4z), S_(xb)—R_(4q), andS_(xb)—R_(4z), these techniques may be used to provide variouscombinations of diastereomers as set forth herein, including, withoutlimitation, those which are essentially free from other diastereomers.

[0230] The invention also provides for methods of making salts ofdiastereomers and pairs thereof. A preferred method for making the saltsof the individual diastereomers and/or pairs thereof first involvesforming these diastereomers of pairs thereof according to the teachingsof the preceding section, in which the chiral plane is first resolvedfollowed by resolution of the sulfoxide atomic chiral center. Salts ofthese resolved diastereomers or pairs thereof may then be formedaccording to various techniques.

[0231] Examples of salts of diastereomers or pairs thereof that may beobtained include, but are not limited to, alkali and alkaline metalsalts. As an example, to obtain optically pure alkali salts of thecompounds of formulae (Ia) and/or (Ib), the diastereomer obtained in amanner described herein, may be treated with: (1) a base, such as forexample, M₁ ⁺OH wherein M₁ is sodium, ammonium, potassium, or lithium,in a aqueous or nonaqueous medium; (2) M₁ ⁺OR² wherein M₁ ⁺ is definedabove, and R² is an alkyl group containing 1 to 4 carbon atoms; or (3)M₁ ⁺NH₂ wherein M₁ ⁺ is defined above. In order to obtain thecrystalline form of the alkali salts, addition of the base M₁ ⁺OH in anon-aqueous medium such as a mixture of 2-butanone and toluene, ispreferred.

[0232] To obtain an optically pure alkaline metal salt of a diastereomeror pair thereof of the compounds of formulae (Ia) and/or (Ib), theoptically pure alkali salt is treated with an aqueous solution of aninorganic alkaline metal salt such as, for example, M₂ ²⁺Cl₂ wherein M₂²⁺ is an alkaline metal such as calcium, magnesium, strontium, barium,and the like, whereupon the alkaline metal salt of the single enantiomeris precipitated. The optically pure alkaline metal salts may also beprepared by treating a single enantiomer of compounds of formulae (Ia)and/or (Ib) with a base such as, for example, M₂ ²⁺(OR³)₂ wherein R³ isan alkyl group containing 1 to 4 carbon atoms, in a non-aqueous solventsuch as alcohol (for alcoholates), or in an ether such astetrahydrofuran.

[0233] A preferred embodiment for the preparation of the magnesium saltsof the S_(xa)—R_(4q) or S_(xa)—R_(4z) diastereomer or pairs thereof ofthe compounds of formulae (Ia) and/or (Ib) polyhydrates comprises: a)treating a magnesium salt of the above individual diastereomer or pairsthereof of such compounds with water at a suitable temperature for asuitable time. The phrase “a suitable temperature” means a temperaturewhich induces the transformation of starting material to product withoutdecomposing any of these compounds. Examples of such suitabletemperatures include, but are not limited to, ambient temperature. By asuitable time is meant a time that results in high conversion of thestarting material into product without causing any decomposition ofeither compound, i.e., results in a good yield. This suitable time willvary depending upon the temperature used in a way well known to peoplein the art. By increasing the temperature, less time is required to givethe desired conversion. The amount of water is generally not crucial andwill depend on the process conditions used. The magnesium salts of theabove diastereomers or pairs thereof of the compounds of formulae (Ia)and/or (Ib) polyhydrates is thereafter separated from the aqueousslurry, for example, by filtration or centrifugation and thereafterdried to constant weight.

[0234] Optionally, the process may comprise: b) oxidizing compounds offormula (II) defined herein, with an oxidizing agent and a chiraltitanium complex, optionally in the presence of a base. The oxidation iscarried out in an organic solvent, for example, toluene ordichloromethane. The crude product is then converted to thecorresponding potassium salt (or, for example, sodium salt as areplacement for each occurrence of potassium salts) by treatment with apotassium source, such as methanolic potassium hydroxide or methanolicpotassium methylate, followed by isolation of the formed salt.

[0235] The resulting potassium salts of the S_(xa)—R_(4q) orS_(xa)—R_(4z) diastereomers, or combinations thereof, of the compoundsof formulae (Ia) and/or (Ib) are thereafter converted to thecorresponding magnesium salts by treatment with a magnesium source, suchas, for example, magnesium sulfate in a lower alkyl alcohol, such asmethanol. The solution is optionally filtered and the precipitation isinitialized by addition of a non-soluble solvent such as acetone. Theproduct is filtered off and optionally washed with water and furtherprocessed as is described in a) above. Alternatively, the potassiumsalts may be treated with a magnesium source, such as, for example,magnesium sulfate in water, and isolation of the magnesium salts of theS_(xa)—R_(4q) or S_(xa)—R_(4z) diastereomers or pairs thereof of thecompounds of formulae (Ia) and/or (Ib) polyhydrates, or any otherconventional technique for transforming a potassium salt to thecorresponding magnesium salt can be used.

[0236] The potassium salts of the S_(xa)—R_(4q) or S_(xa)—R₄diastereomers, or pairs thereof, of the compounds of formulae (Ia)and/or (Ib) are suitable intermediates in the preparation of themagnesium salts of these. diastereomers or pairs thereof. The potassiumsalts of these diastereomers may also be used as active components inpharmaceutical formulations to be used in the treatment of variousdiseases described herein, particularly gastric acid related diseases.

[0237] To establish and quantitate the ratio of the 5- and 6-methoxyisomers of omeprazole API, including the novel ratios of such isomers ofthe present invention (the “modified omeprazole compounds”), a Ramanspectrographic method was developed using a FT-Raman spectrometer(Nicolet Nexus 670 with an FT-Raman accessory, 1064 nm laser, and a stepand repeat sampling device; Nicolet Instruments Corp., Madison, Wis.).The present method is conducted in three steps: preparation ofstandards, establishing a standard curve, and analysis of samples.

[0238] Typically, a minimum of 4 to 5 standards are prepared. In thepresent method, seven standards were prepared using the methods setforth in Examples 1, 1a, 36, 37, 41, and 44 herein, plus a commerciallyavailable sample of omeprazole purchased from the United StatesPharmacopia (USP). In addition to the USP standard, it is necessary touse a standard which is very low in 5-methoxy isomer concentration,preferably in pure form, one which has a high concentration of 5-methoxyisomer such as in the range of about 40%, and a series of at least twoother standards distributed over the range from about 5% to about 25%.To establish the standard curve, each standard is run in at leasttriplicate using the step and repeat sampling device operating in thecontinuous mode with 15 replicates for each standard preparation and 500scans per replicate, using a resolution of 2 cm⁻¹, and a laser power ofabout 0.7 watt, under instrumental parameters set to generate anacceptable S/N.

[0239] For each of the selected standards, other than the “pure”6-methoxy isomer, a deconvolution algorithm (self-Fourier deconvolutionsoftware; such as, for example, TQ Analyst™ from Nicolet InstrumentsCorporation) is used to deconvolute the peak areas of the peaks at about1365 cm⁻¹ (the 5-methoxy isomer) and 1354 cm⁻¹ (the 6-methoxy isomer).The pure 6-methoxy isomer (Example 1a) only shows a simple peak at 1354cm⁻¹ and as such the percent 6-methoxy isomer is set at a concentrationof 100%. Using such an algorithm, the area percent of the 6-methoxyisomer of each standard having both the 5- and 6-methoxy isomer isdetermined. The standard deviation for each set of replicates is lessthan about 0.7% and the average, standard deviation for the average ofall runs and replicates of a given standard is less than about 0.7% orthe resulting data should be investigated.

[0240] A software program capable of analyzing Raman spectra in apartial least squares format such as, for example, Nicolet's TQAnalyst™, is used to generate a standard curve using the averagedetermined percent 6-methoxy isomer values and the spectrum of a givenstandard. Correlation coefficients should be at or above about 0.98among all standards.

[0241] Each API sample is then analyzed using the method similar to thatdescribed for establishing the standards, except at least triplicatepreparations with at least five replicates per sample preparation, andat least 100 scans per replicate with triplicate preparations persample. Using the above-referenced partial least squares analysis, thepercent 6-methoxy isomer, and thus the percent 5-methoxy isomer isdetermined for each scan and the average of the spectra is calculated.The standard deviation (SD) for each set of replicates is less thanabout 1.0%, and the average standard deviation of all runs andreplicates of a given sample is less than about 1.0%. If the standarddeviation is above 1.0%, the results should be investigated. Highstandard deviation values are an indication of variability which may becaused by small amounts of sample burning. If this is suspected, thepreparation should be run again.

[0242] Using the methods taught above, results from establishing thestandard curve are as follows: Standard Example/Sample % 5-isomer %6-isomer Example 1a 0.000 100.000 Example 1 5.875 94.125 StandardDeviation (SD) 0.338 USP 7.250 92.750 SD 0.556 Example 37 12.246 87.754SD 0.505 Example 36 16.005 83.995 SD 0.501 Example 41 16.414 83.587 SD0.597 Example 44 41.258 58.742 SD 0.328

[0243] Using the API quantitative method taught above, three randomlyselected lots of omeprazole API (commercial API lots from Merck andCompany, Raway, N.J.) were analyzed. Results are as follows: Sample/Lot% 5-isomer % 6-isomer 01 7.50 92.50 SD 0.75 02 8.02 91.98 SD 0.56 037.61 92.39 SD 0.81

[0244] Results from these data via the above-described quantitativemethod again confirms that the compound known as omeprazole is not5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole as previously designated, but, rather, using the USPstandard for omeprazole as well as three lots of omeprazole API from thesole United States manufacturer of omeprazole, is in fact(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazolein a tightly defined ratio of about 93:7±about 2% of the 6-methoxyisomer and 5-methoxy isomer, respectively. Accordingly, the presentinvention provides pure6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole(6-methoxy omeprazole), which is essentially free of5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole,and(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazolein the ratios set forth herein, and the methods and formulations furtherset forth herein.

[0245] Furthermore, an additional method for establishing the ratio ofthe 5- and 6-methoxy isomers of omeprazole API, albeit less precise thanthe quantitative FT-Raman method previously described herein, as well asratio of the 5- and 6-methoxy isomers in omeprazole drug product wasdeveloped. This method also used an FT-Raman spectrometer (Nicolet Nexus670 with an FT-Raman accessory, 1064 nm laser, and a step and repeatsampling device). This method, too, is conducted in three stages:preparation of standards, establishing a standard curve, and analysis ofsamples.

[0246] Typically a minimum of 4 to 5 standards are prepared. The presentFT-Raman method for API and drug product analysis uses the same methodset forth above to prepare and establish the standard curve, includingpreferred aspects, as the method set forth for the more quantitative APImethod relative to the number of preparations, replicates, and scans perreplicate of each standard, resolution, sampling device, deconvolutionof standard peaks, determination of peak area, and standard deviationfor each set of replicates and the average of all runs and replicates ofa given standard.

[0247] Rather than a partial least squares analysis, however, a softwareprogram capable of analyzing Raman spectra in a corrected classicalleast squares format, for example, Nicolet's TQ Analyst™, is used togenerate a standard curve using the average determined percent 6-methoxyisomer values and the peak height ratio of a given pair of peaks in astandard. In general, the method is performed by a ratio of a peakrelated to the 6-methoxy isomer (about 1627 cm⁻¹) to a suitable internalomeprazole band (about 1587 cm⁻¹). In the event the presence andmagnitude of matrices from pharmaceutical excipients in drug productinterfere with the resolution of the peak related to the 6-methoxyisomer and/or the preferred internal omeprazole band, other sets ofbands at such as, for example, about 1587 cm⁻¹ and 1201 cm⁻¹,respectively, and 1185 cm⁻¹ and 1512 cm⁻¹, respectively, are used.Correlation coefficients of the standard curve are at or above about0.95 among all standards.

[0248] For omeprazole API, each sample is prepared under the sameinstrument conditions as the standards except it is preferred to use atleast triplicate preparations with at least five replicates per samplepreparation and at least 100 scans per replicate. Using theabove-referenced corrected classical least squares analysis, the percent6-methoxy isomer, and thus the percent 5-methoxy isomer, is determinedfor each scan, and the average of the 15 spectra is calculated. Thestandard deviation for each set of replicates is less than about 2.0%,and the average standard deviation of all runs and replicates of a givensample is less than about 2.0% or the sample run should be investigated.

[0249] For omeprazole drug product, capsules and tablets are similarlyprepared. For capsules, a sufficient number of capsules, preferablyabout 5-10 capsules, are opened and the omeprazole beads are emptiedinto an appropriate container. The container is gently rolled to mix thebeads or powder, as appropriate, from the various capsules to provide agenerally homogeneous blend. For tablets, a sufficient number oftablets, preferably about 5-10 tablets, are gently ground (vigorousgrinding may affect the ratio of 5- and 6-methoxy isomers inomeprazole), and blended to provide a generally homogeneous blend of theground material.

[0250] Each appropriate composite sample is analyzed under the sameinstrument conditions as the standards, adjusting to an appropriatelaser wattage to compensate for the presence of excipients. For FT-Ramananalysis, each sample preparation (the composite from capsules ortablets) is run using at least triplicate preparations with at leastthree replicates and at least 500 scans per replicate. Using a correctedclassical least squares analysis, the percent 6-methoxy isomer, and thusthe percent 5-methoxy isomer, is determined for each scan, and theaverage of the 9 spectra is calculated. The standard deviation for eachset of replicates is less than about 3.0%, and the average standarddeviation of all runs of a given sample is less than about 3.0% or thesample run should be investigated.

[0251] Although the partial least squares method described above for APIis more accurate than this classical least squares method, thedeconvolution of the peaks related to the 5- and 6-methoxy isomersremains the same for both methods and, thus, the standards curve used todevelop each remains the same. Results from API sample analysis with theclassical least squares method shows a slightly lower bias than theresults from using the partial least squares method, but the data fromthe partial least squares analysis of omeprazole API samples confirmsthe validity of this method for a generally quantitative method fordetermining the ratio of 5- and 6-methoxy isomers in omeprazole drugproduct (Prilosec®) which is commercially available via prescription.The drug. product used in the present classical least squares method wasprovided by Merck and Company, Raway, N.J.

[0252] Results from API analysis of the three randomly selected lots ofomeprazole API used in the previous partial least squares werecalculated using the classical least squares methods are as follows:Sample/Lot % 5-isomer % 6-isomer 01 6.14 93.86 SD 0.97 02 6.56 93.44 SD1.10 03 6.40 93.60 SD 1.21

[0253] When applying this classical least squares analytical method todrug product, it was unexpectedly discovered that the ratio of 5- and6-methoxy isomers of omeprazole, and thus, it is believed for othercompounds represented by formulae (Ia) and/or (Ib), as activepharmaceutical ingredient(s) can be significantly influenced by amultitude of factors during the preparation of drug product (finalpharmaceutical formulations for administration, preferably in unitdosage form).

[0254] For the sole omeprazole drug product registered by the U.S. Foodand Drug Administration and sold in the United States (Prilosec®), theratio of the 6- and 5-methoxy isomers in API typically shifts from aratio of about 93:7 (+/−about 2%), respectively, to a ratio in drugproduct of about 86:14 (+/−about 3%), respectively. Factors such asmechanical manipulation (e.g., grinding or, potentially, aggressivesieving) and, particularly the use of commonly used wet granulationprocesses during drug product preparation have likely contributed tothis significant and unexpected shift. Accordingly, shifts from the morethermodynamically stable compounds of the present invention having ahigher percentage of the 6-methoxy isomer (with the pure 6-methoxyisomer being preferred) to the less stable compounds of the presentinvention having increasing concentrations of the 5-methoxy isomer inthe same composition can affect the stability and dissolution profilesof drug product. Compounds and pharmaceutical formulations of thepresent invention having such higher percentage of such 6-methoxy isomerprovide greater stability whereas those having such increasingpercentage of such 5-methoxy isomer provide more rapid dissolution.

[0255] Using the classical least squares analytical method describedabove, results for Prilosec® drug product are as follows: PrilosecDosage % 5-isomer % 6-isomer 20 mg 14.7 85.3 SD 2.3 20 mg 14.5 85.5 SD2.0 20 mg 14.7 85.3 SD 3.0 40 mg 13.2 86.8 SD 1.6 40 mg 12.9 87.1 SD 0.910 mg 13.6 86.4 SD 2.8 10 mg 13.3 86.7 SD 2.4

[0256] In addition, a homogeneous dry blend pharmaceutical formulationof the above-referenced omeprazole API from Merck and Company andmannitol was prepared with an equivalent dose of 20 mg per dosage form,preferably an enterically coated capsule as set forth herein. Theabove-referenced FT-Raman analytical method was used to determine theratio of a composition of6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleto5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazolein such pharmaceutical formulation compared to the ratio of suchcompounds in the corresponding active pharmaceutical ingredient usingthe classical least squares FT-Raman analytical method for API set forthabove. It was unexpectedly discovered that the ratio of the twocompounds in API (about 93-94%:6-7% for the 6-methoxy isomer to the5-methoxy isomer, respectively) was essentially the same as the ratio ofthe composition of the 6-methoxy isomer to the 5-methoxy isomer in thedry blended pharmaceutical formulation. These data were unexpectedbecause, as demonstrated above, the percentage of the 6-methoxy isomerof omeprazole significantly decreases and the percentage of the5-methoxy isomer significantly increases when such a composition of suchMerck and Company API is formulated as Prilosec® drug productAccordingly, in order to utilize the benefits of higher percentages ofthe 6- and 5-methoxy isomers of omeprazole as set forth herein, and tomaintain the desired ratio of the 6- and 5-methoxy isomers ofcompositions and complexes of the present invention in the appropriatedrug product, including the unit dosage forms taught herein, the presentinvention further provides pharmaceutical formulations comprising anon-toxic amount of a composition of at least one compound representedby formula (Ia) and optionally, at least one compound represented byformula (Ib) or one or more pharmaceutically acceptable salts, solvates,hydrates, or combinations of such compounds represented by formulae (Ia)and (Ib), and at least one non-aqueous pharmaceutically acceptablecarrier, diluent, or excipient, wherein the ratio of said compoundrepresented by formula (Ia) and said compound represented by formula(Ib) in said composition is essentially the same as the ratio of saidcompound is represented by formula (Ia) and said compound is representedby formula (Ib) in the active pharmaceutical ingredient used in saidpharmaceutical formulation.

[0257] As used in this context, the term “essentially the same” meansthat the API to active ingredient in drug product ratio of 6- to5-methoxy isomers of compounds represented by formulae (Ia) and (Ib),respectively, does not vary by more than +/−five percentage points(w/w). For example, for an API having a 6- to 5-methoxy isomer ratio ofabout 95:5 (w/w), the active ingredient ratio in the corresponding drugproduct is from about 100:0 to about 90:10 (w/w), respectively.

[0258] Typical non-aqueous carriers, diluents, and excipients include,for example, mannitol, lactose, and the like. In addition, any of thedry blend formulations taught herein can optionally include one or morestabilizing agents which are well known in the art. A preferredstabilizing agent is pelletized sodium hydroxide which is homogeneouslyblended with the homogeneous dry blended formulations of the presentinvention prior to preparation of the final dosage form. Preferred finaldosage forms (drug product) of these dry blended pharmaceuticalformulations are those which are set forth herein, including preferredunit dosage forms and dosage strengths.

[0259] A preferred compound represented by formula (Ia) is6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole,in pure form, essentially free of5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole,and as a composition with5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleas taught herein. A preferred compound represented by formula (Ib) is5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole.

[0260] The present invention further provides pharmaceuticalformulations wherein said preferred6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleis present in said compositions at a concentration less than about 83%(w/w) and, in another preferred embodiment, in a concentration greaterthan about 89% (w/w), each relative to the corresponding 5-methoxyisomer such that the sum of such 6-methoxy isomer and such 5-methoxyisomer equals 100%.

[0261] Further provided are methods for essentially maintaining thedesired active ingredient ratio of a composition comprising a compoundrepresented by formula (Ia), preferably6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole,and, optionally, a compound represented by formula (Ib), preferably5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole,or one or more pharmaceutically acceptable salts, solvates, hydrates, orcombinations of such compounds represented by formulae (Ia) and (Ib), ina pharmaceutical formulation compared to the ratio of said compoundsrepresented by formulae (Ia) and (Ib) in the active pharmaceuticalingredient used in said pharmaceutical formulation comprising dryblending said composition of active pharmaceutical ingredient with atleast one non-aqueous pharmaceutically acceptable carrier, diluent, orexcipient. Preferred compositions and ratios of said compounds are asset forth above for drug product and herein.

[0262] Such dry blend pharmaceutical formulations of the presentinvention, particularly in unit dosage form, are used for treating thedisease states described herein. As such, the present invention furtherprovides methods of treating a subject (e.g., mammals, particularlyhumans) comprising administering to a subject in need of treatment(including prophylaxis) of gastric acid related diseases/disease statesvia the inhibition of gastric acid, as further discussed herein, atherapeutically effective, non-toxic amount of the aforementionedpharmaceutical formulations. Preferred compounds and compositions, asactive ingredients, unit dosage forms, and dosage strengths are as setforth herein.

[0263] The present invention also encompasses other pharmaceuticalformulations comprising at least one active pharmaceutical ingredient ofthe present invention and at least one pharmaceutically acceptablecarrier, diluent, or excipient, or combination thereof, the selection ofwhich is known to the skilled artisan. For the purposes of theinvention, the term “active ingredient” refers to any of the embodimentsset forth herein referring to the compound(s) of formulae (Ia) and/or(Ib), diastereomers thereof, any combinations of diastereomers thereof,pharmaceutically acceptable salts thereof, along with complexes,hydrates, solvates, and polymorphs of any of the above, as well as anycombinations thereof as well as compositions thereof. Prodrugs of any ofthese active pharmaceutical ingredients may also be employed for thepurposes of the invention, most preferably as part of a pharmaceuticalformulation wherein said prodrug is metabolized, in vivo, to thepharmaceutically active moiety, although their use in other embodimentsmay be carried out. The term “active ingredient” also encompasses, inone embodiment, a solid pharmaceutical composition of the presentinvention which is blended with at least one pharmaceutically acceptableexcipient, diluted by an excipient or enclosed within such a carrierthat can be in the form of a capsule, sachet, tablet, buccal, lozenge,paper, or other container. When the excipient serves as a diluent, itmay be a solid, semi-solid, or liquid material which acts as a vehicle,carrier, or medium for the active ingredient. Thus, the formulations canbe in the form of tablets, pills, powders, elixirs, suspensions,emulsions, solutions, syrups, capsules (such as, for example, soft andhard gelatin capsules), suppositories, sterile injectable solutions, andsterile packaged powders.

[0264] Examples of suitable excipients include, but are not limited to,starches, gum arabic, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include lubricating agents such as, forexample, talc, magnesium stearate and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl- andpropyl hydroxybenzoates; sweetening agents; or flavoring agents.Polyols, buffers, and inert fillers may also be used. Examples ofpolyols include, but are not limited to: mannitol, sorbitol, xylitol,sucrose, maltose, glucose, lactose, dextrose, and the like., Suitablebuffers encompass, but are not limited to, phosphate, citrate,tartarate, succinate, and the like. Other inert fillers which may beused encompass those which are known in the art and are useful in themanufacture of various dosage forms. If desired, the solidpharmaceutical compositions may include other components such as bulkingagents and/or granulating agents, and the like. The compositions of theinvention can be formulated so as to provide quick, sustained, ordelayed release of the active ingredient after administration to thepatent by employing procedures well known in the art.

[0265] In the event that the above formulations are to be used forparenteral administration, .such a formulation typically comprisessterile aqueous and non-aqueous injection solutions comprising theactive ingredient, for which preparations are preferably isotonic withthe blood of the intended recipient. These preparations may containanti-oxidants, buffers, bacteriostats, and solutes which render theformulation isotonic with the blood of the intended recipient. Aqueousand non-aqueous sterile suspensions may include suspending agents andthickening agents. The formulations may be presented in unit-dose ormulti-dose containers, for example sealed ampules and vials.

[0266] Extemporaneous injection solutions and suspensions may beprepared from sterile powders, granules and tablets of the kindpreviously described.

[0267] In certain embodiments of the invention, the active ingredientmay be made into the form of dosage units for oral administration. Theactive ingredient may be mixed with a solid, pulverant carrier such as,for example, lactose, saccharose, sorbitol, mannitol, starch,amylopectin, cellulose derivatives or gelatin, as well as with anantifriction agent such as, for example, magnesium stearate, calciumstearate, and polyethylene glycol waxes. The mixture is then pressedinto tablets. If coated tablets are desired, the above prepared core maybe coated with a concentrated solution of sugar, which may contain gumarabic, gelatin, talc, titanium dioxide, or with a lacquer dissolved involatile organic solvent or mixture of solvents. To this coating,various dyes may be added in order to distinguish among tablets withdifferent active compounds or with different amounts of the activecompound present.

[0268] Soft gelatin capsules may be prepared in which capsules contain amixture of the active ingredient and vegetable oil or non-aqueous, watermiscible materials such as, for example, polyethylene glycol and thelike. Hard gelatin capsules may contain granules of the activeingredient in combination with a solid, pulverulent carrier, such as,for example, lactose, saccharose, sorbitol, mannitol, potato starch,corn starch, amylopectin, cellulose derivatives, or gelatin.

[0269] Dosage units for rectal administration may be prepared in theform of suppositories which may contain the active ingredient in amixture with a neutral fat base, or they may be prepared in the form ofgelatin-rectal capsules which contain the active substance in a mixturewith a vegetable oil or paraffin oil.

[0270] Liquid preparations for oral administration may be prepared inthe form of syrups or suspensions, e.g., solutions containing an activeingredient, sugar, and a mixture of ethanol, water, glycerol, andpropylene glycol. If desired, such. liquid preparations may containcoloring agents, flavoring agents, and saccharin.

[0271] Thickening agents such as carboxymethylcellulose may also beused.

[0272] Solutions for parenteral administration by injection may beprepared as an aqueous solution of a water soluble, pharmaceuticallyacceptable salt of the active ingredient. These solutions may alsocontain stabilizing agents and/or buffering agents and may bemanufactured in different dosage unit ampules.

[0273] Tablets for oral use are typically prepared in the followingmanner, although other techniques may be employed. The solid substancesare gently ground or sieved to a desired particle size, and the bindingagent is homogenized and suspended in a suitable solvent. The activeingredient and auxiliary agents are mixed with the binding agentsolution. The resulting mixture is moistened to form a uniformsuspension. The moistening typically causes the particles to aggregateslightly, and the resulting mass is gently pressed through a stainlesssteel sieve having a desired size. The layers of the mixture are thendried in controlled drying units for determined length of time toachieve a desired particle size and consistency. The granules of thedried mixture are gently sieved to remove any powder. To this mixture,disintegrating, anti-fiction, and ant-adhesive agents are added.Finally, the mixture is pressed into tablets using a machine with theappropriate punches and dies to obtain the desired tablet size. Theoperating parameters of the machine may be selected by the skilledartisan.

[0274] Typically, preparation of lozenge and buccal dosage forms areprepared by methods known to one of ordinary skill in the art.

[0275] In a particular embodiment, the active ingredient may be presentin a core surrounded by one or more layers including an enteric coatinglayer. With respect to formation of the core, the active ingredient istypically mixed with inert, preferably water soluble, conventionalpharmaceutically acceptable constituents to obtain the preferredconcentration of the active ingredient in the final mixture with analkaline reacting, otherwise inert, pharmaceutically acceptablesubstance (or substances), which creates a “micro-pH” around eachparticle of active compound of not less than a pH of 7, preferably notless than a pH of 8, when water is adsorbed to the particles of themixture or when water is added in small amounts to the mixture. Suchsubstances can be chosen among, but are not limited to, sodium,potassium, calcium, magnesium, and aluminum salts of phosphoric acid,carbonic acid, citric acid, or other suitable weak inorganic or organicacids; substances typically used in antacid preparations such asaluminum, calcium, and magnesium hydroxides; magnesium oxide orcomposite substances such as, for example, Al₂O₃.6MgO CO₂.12H₂O(Mg₆Al₂.(OH)₁₆CO₃4H₂O), MgO.Al₂O₃, 2SiO₂.nH₂O, wherein n is notnecessarily a whole number and may be less than 2, or similar compounds;organic pH-buffering substances such as trihydroxymethylamino-methane orother similar, pharmaceutically acceptable pH-buffering substances. Thestabilizing high pH-value in the powder mixture can also be achieved byusing an alkaline reacting salt of the active compound such as, but notlimited to, sodium, potassium, magnesium, and calcium salts of activeingredient, either alone or in combination with a conventional bufferingsubstance as previously described.

[0276] The powder mixture may then be formulated into small beads, i.e.,pellets or tablets, by conventional pharmaceutical procedures. Thepellets, tablets, or gelatin capsules may then be used as cores forfurther processing.

[0277] The reacting cores containing the active ingredient may beseparated from the enteric coating polymer(s) containing free carboxylgroups, that otherwise is capable of causing degradation/discolorationof the active compound during the coating process or during storage. Thesubcoating layer (i.e., the separating/barrier layer), also serves as apH-buffering zone to contain sufficient buffer capacity such thathydrogen ions diffusing from the outside in towards the core can reactwith hydroxyl ions diffusing from the core towards the surface of thecoated article. The pH-buffering properties of the separating layer canbe further strengthened by introducing in the layer substances chosenfrom a group of compounds usually used in antacid formulations describedabove. The separating layer usually consists of one or more watersoluble inert layers, optionally containing pH-buffering substances.

[0278] The separating layer(s) can be applied to the cores, typically inthe form of pellets or tablets, by conventional coating procedures in asuitable coating pan or in a fluidized bed apparatus using water and/orconventional organic solvents for the coating solution. The material forthe separating layer may be chosen among the pharmaceutically acceptablewater soluble, inert compounds or polymers used for film-matingapplications such as, for example, sugar, polyethylene glycol,polyvinylpyrrollidone, polyvinyl alcohol, hydroxypropyl cellulose,hydroxymethyl cellulose, hydroxypropyl methylcellulose, or the like. Thethickness of the separating layer may be determined according to theskilled artisan.

[0279] In the case of tablets, another method to apply the coating canbe performed by the dry coating technique. First, a tablet containingthe active ingredient is compressed as described herein. Around thistablet, another layer is compressed using a suitable tableting techniquemachine. The outer, separating layer, contains pharmaceuticallyacceptable, in water soluble or in water, rapidly disintegrating tabletexcipients. Conventional plasticizers, pigments, titanium dioxide talc,and other additives may be included in the separating layer. Inembodiments encompassing gelatin capsules, the gelatin capsule itselfserves as a separating layer.

[0280] The enteric coating layer is typically applied on to thesub-coated cores by conventional coating techniques such as, forexample, pan coating or fluidized bed coating using solutions ofpolymers in water and/or suitable organic solvents or by using latexsuspensions of the polymers. Enteric coating polymers that can be usedinclude, for example, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate,carboxymethylethylcellulose, copolymerized methacrylic acid/methacrylicacid methyl esters such as, for example, compounds known under the tradename Eudragit®L 12,5 or Eudragit®L 100 (Röhm Pharma of Darmstadt,Germany), or other similar compounds. The enteric coating can also beapplied using water-based polymer dispersions, e.g. Aquateric® (FMCCorporation of Chicago, Ill.), Eudragit®L100-55 (Röhm Pharma ofDarmstadt, Germany), Coating CE 5142 (BASF of Mount Olive, N.J.). Theenteric coating layer can optionally contain a pharmaceuticallyacceptable plasticizer such as, for instance, cetanol, triacetin, citricacid esters such as, for example, those known under the trade nameCitroflex® (Pfizer of New York, N.Y.), phthalic acid esters, dibutylsuccinate or similar plasticizers. The amount of plasticizer is usuallyoptimized for each enteric coating polymer(s). Dispersants such as talc,colorants and pigments may also be included in the enteric coatinglayer.

[0281] Thus, the formulations described by the above embodimentscomprise cores containing at least one active ingredient describedherein, optionally mixed with an alkaline reacting compound, or corescomprising a salt of at least one active ingredient or one or moreenantiomers thereof as taught herein, or one or more pharmaceuticallyacceptable salts, hydrates, solvates, polymorphs, or combinationsthereof, optionally mixed with an alkaline reacting compound. Thealkaline reacting core material and/or alkaline salt of the activeingredient is believed to potentially enhance the stability of theactive ingredient. The cores suspended. in water form a solution or asuspension which has a pH which is higher than that of a solution inwhich the polymer used for enteric coating is just soluble. The coresmay be coated with an inert reacting water soluble or in water rapidlydisintegrating coating, optionally containing a pH-buffering substance,which separates the cores from the enteric coating. Without thisseparating layer, the resistance towards gastric juice may be too shortand/or the storage stability of the dosage form would be unacceptablyshort. The sub-coated dosage form is finally coated with an entericcoating rendering the dosage form insoluble in acid media, but rapidlydisintegrating/dissolving in neutral to alkaline media such as, forinstance, the liquids present in the proximal part of the smallintestine.

[0282] The final dosage form encompassing the above embodiments may beeither an enteric coated tablet or capsule or in the case of entericcoated pellets, pellets dispensed in hard gelatin capsules or sachets orpellets formulated into tablets. It is desirable for long term stabilityduring storage that the water content of the final dosage formcontaining the active ingredient (enteric coated tablets, capsules orpellets) be kept low. As a consequence, the final package containinghard gelatin capsules filled with enteric coated pellets preferably alsocontain a desiccant, which reduces the water content of the gelatinshell to a level where the water content of the enteric coated pelletsfilled in the capsules does not exceed a certain level.

[0283] Accordingly, the compounds and compositions of the presentinvention are preferably formulated in a unit dosage form, each dosagecontaining from about 5 mg to about 60 mg, and more preferably theamount set forth herein. The term “unit dosage form” refers tophysically discrete units, such as capsules or tablets suitable asunitary dosages for human patients and other mammals, each unitcontaining. a predetermined quantity of one or more active ingredient(s)calculated to produce the desired therapeutic effect, in associationwith at least one pharmaceutically acceptable carrier, diluent,excipient, or combination thereof. Generally, preferred dosages ofactive ingredient(s) in such unit dosage forms are from about 8 mg toabout 10 mg, about 16 mg to about 20 mg, and about 32 mg to about 40 mg,especially 10 mg, 20 mg, and 40 mg per dosage unit.

[0284] In another aspect, the invention provides a complex comprisingany of the active ingredients as defined hereinabove and at least onecyclodextrin. Most preferably, the complex is in the form of aninclusion complex. As used herein, the term “active ingredient” refersto any of the embodiments set forth herein referring to the compound(s)of formulae (Ia) and/or (Ib), diastereomers thereof, any combinations ofdiastereomers thereof, pharmaceutically acceptable salts thereof, alongwith complexes, hydrates, solvates, and polymorphs of any of the above,as well as any compositions thereof, and combinations of any of theabove. For the purposes of the invention, the term “cyclodextrin” is tobe broadly construed and include, without limitation,alpha-cyclodextrins, beta-cyclodextrins, and gamma-cyclodextrins. Anexample of a description of cyclodextrins is provided in The MerckIndex, 12^(th) Ed., (p. 458) 1996. As known in the art, cyclodextrinsare cyclic oligosaccharides typically consisting of 6, 7, or 8 glucoseunits. The glucose units are linked by alpha-1,4-glucosidic bonds. As aconsequence of the chair formation of the sugar units, all secondaryhydroxyl groups (e.g., at C₂ and C₃) are located on one side of thering, while all the primary hydroxyl groups at C₆ are situated on theother side. As a result, the external faces are hydrophilic, making thecyclodextrins water-soluble. In contrast, the cavities of thecyclodextrins are hydrophobic, since they are lined by the hydrogen ofatoms C₃, C₅, and by ether-like oxygens. Also encompassed under thedefinition of cyclodextrin are derivatives of cyclodextrins. In variousembodiments, the 18 to 24 hydroxyl groups of the respective cyclodextrinmolecules are the starting points for the synthesis of such derivatives.Using known techniques, methyl-, ethyl-, hydroxyethyl-, hydroxymethyl,and hydroxypropyl substituted cyclodextrins may be utilized.

[0285] Examples of cyclodextrins that may be used include, withoutlimitation, hydropropyl-beta-cyclodextrin,hydroxyethyl-beta-cyclodextrin, G2-alpha-cyclodextrin,G2-beta-cyclodextrin, gamma-cyclodextrin, and methyl-beta-cyclodextrin.A particularly preferred cyclodextrin is hydroxypropyl-beta-cyclodextrin(HPβCD). Combinations of cyclodextrins may also be employed for thepurposes of the invention. Although not intending to be bound by any onetheory, it is believed that hydrogen and/or van der Waals bonding forcesare responsible for the bonding within the complex with the hydrogenbonding being present for the portion of the molecule exposed outside ofthe cyclodextrin ring. Theories on bonding types and strengths aredocumented in the literature and are known by the skilled artisan.

[0286] Although the use of cyclodextrins as solubilizing agents isgenerally known in the pharmaceutical arts, it is rarely, if ever, knownwhat affect cyclodextrins will have on the bioavailability or otherbiological characteristics of the active ingredient(s) used with suchone or more cyclodextrins. It was unexpectedly discovered that theaddition of cyclodextrin to omeprazole API significantly increases bothC_(max) and, more importantly, AUC compared to an omeprazole formulationwhich does not include cyclodextrin. The solubility characteristicsamong compounds of the present invention will vary, but it is believedthat such compounds have improved biological characteristics whenformulated with cyclodextrins as taught herein.

[0287] Accordingly, the invention further encompasses compositions ofmatter comprising any of the active ingredients as defined hereinaboveand at least one cyclodextrin. In one embodiment, the cyclodextrin andthe active ingredient may be present in the form of a complex. Inanother embodiment, the cyclodextrin may be in free form.

[0288] In another aspect, the invention provides pharmaceuticalformulations, preferably in unit dose form, comprising at least oneactive ingredient as defined hereinabove, at least one cyclodextrin, andat least one pharmaceutically acceptable carrier, diluent, or excipientthat are defined herein, the selection of which are known to the skilledartisan. These pharmaceutical formulations can be present in any of thespecific forms set forth herein or as known in the pharmaceutical arts,as appropriate. Particularly preferred are enteric coated oral dosageforms comprising at least one active ingredient and at least. onecyclodextrin, preferably, hydroxypropyl-β-cyclodextrin. The aboveformulations may be prepared by using techniques known in the artincluding, without limitation, lyophilization, spray drying, and spraygranulation. In the formulations, it is preferred that the activeingredient and the cyclodextrin be present in the form of an inclusioncomplex.

[0289] In one embodiment, hard and soft capsules comprising such atleast one cyclodextrin and such active ingredient(s) are particularlypreferred for the purposes of the invention. These formulations may beformed according to methods known to one skilled in the art usingaccepted ingredients (e.g., excipients, carriers, and/or diluents) suchas, without limitation, those described hereinabove. As an example, atleast one pharmaceutically acceptable, non-toxic solubilizing agent maybe employed. Such readily available solubilizing agents are well knownin the art and are typically represented by the family of compoundsknown as polyethylene glycols (PEG) having molecular weights from about200 to about 8,000. When a liquid is desired for the final formulationor a liquid is to be used to fill soft capsules, preferably soft gelatincapsules, the preferred molecular weight range of PEG is from about 200to about 600 with PEG 400 being especially preferred. When a semi-solidis preferred, especially for filling a hard capsule, preferably a hardgelatin capsule, a preferred PEG molecular weight is about 3350 while anespecially preferred combination includes 3350 molecular weight PEG plussufficient 400 molecular weight PEG to improve capsule fillingcharacteristics. Enterically coated hard gelatin capsules areparticularly preferred with the higher molecular weight (e.g., 3350)PEG.

[0290] The formulation may comprise various amounts of cyclodextrin andactive ingredient. Preferably, the complex comprises these components ina molar ratio of active ingredient to cyclodextrin ranging from about1:4 to about 1:28, more preferably from about 1:4 to about 1:10.

[0291] The invention also provides methods of treating a subject (e.g.,mammal, particularly humans) comprising administering to a subject inneed of such treatment a therapeutically effective amount of at leastone active ingredient, formulation thereof, or unit dose forms thereof,each as described herein. The active ingredient(s) may be used to treata number of disorders. Generally, such active ingredients are useful forinhibiting gastric acid secretions and for preventing and treatinggastric acid related diseases in mammals, particularly humans. Thesediseases include, but may not be limited to, duodenal ulcer, H. pyloriinfection, gastric ulcer, gastro-esophageal reflux disease and symptomsassociated therewith (e.g., heartburn), erosive esophagitis,pathological hypersecretary conditions (e.g., Zollinger-Ellisonsyndrome, endocrine adenomas and systematic mastocytosis), gastritis,duodenitis. The active ingredient(s) may also be used for the treatmentof other gastrointestinal disorders where gastric acid inhibitory effectis desirable (e.g., in patients on NSAID therapy, in patients with NonUlcer Dyspepsia). The active ingredient(s) may also be used in patentsin intensive care situations, in patients with acute uppergastrointestinal bleeding, pre and post-operatively to prevent acidaspiration of gastric acid and to prevent and treat stress ulceration.Moreover, the active ingredient(s) may be useful in the treatment ofpsoriasis as well as in the treatment of Heliocobacter infections anddiseases related to those. The active ingredient(s) may also be used forthe treatment of inflammatory conditions in mammals and particularlyhumans, particularly those involving lysozymal enzymes.

[0292] As used herein, the term “treatment”, or a derivative thereof,contemplates partial or complete inhibition of the stated disease state.such as, for example, duodenal ulcer, when an active ingredient of thepresent invention is administered prophylactically or following theonset of the disease state for which such active ingredient of thepresent invention is administered. For the purposes of the presentinvention, “prophylaxis” refers to administration of the activeingredient(s) to a mammal to protect the mammal from any of thedisorders set forth herein, as well as others. Other examples of suchconditions that may be treated include rheumatoid arthritis and gout.

[0293] Other disorders that may be prevented or treated in accordancewith the invention including schizophrenia, symptoms of bradyphremia inParkinson's Disease, elevated intraocular pressure in the eye of apatient, and microbial infections associated with gram-negative bacteria(especially microaerophilic bacteria), bacteria of the genusCampylbacter represented by C. pylori. The treatment of infectiousdiseases due to such bacteria in mammalian animals including withoutlimitation humans, cattle, horse, dog, mouse, rat, the control andinhibition of environmental pollution, and disinfectant use may beachieved by virtue of the invention.

[0294] The active ingredient(s) disclosed herein possess worthwhiletherapeutic properties as gastric acid secretion inhibitors asdemonstrated by the following tests. To determine the gastric acidsecretion inhibitory properties, experiments are performed on consciousdogs provided with gastric fistulas of conventional type and duodenalfistulas, the latter ones used for direct intraduodenal administrationof the active ingredient(s). After 18 hours starvation and deprivationof water the dogs are given a subcutaneous infusion of pentagastrin (1-4nmol/kg/h) lasting for 6 to 7 hours. Gastric juice is collected inconsecutive 30 minute samples. An aliquot of each sample is titratedwith 0.1N NaOH to pH 7 for titrable acid concentration using anautomatic titrator and pH-meter. Acid output is calculated as mmol H⁺/60minutes. The active ingredient(s), suspended in 0.5 percent methylcellulose, is given intraduodenally in doses from 4 to 20 nmol/kg whenthe secretory response to pentagastrin reaches a steady level. Thisembodiment may also be used for prophylaxis by administration of theactive ingredient prior to pentagastrin.

[0295] The typical active daily dose of the active ingredients(s) willdepend on various factors such as, for example, the individualrequirement of each patient, the route of administration, and thedisease. An attending physician may adjust the dosage rate based onthese and other criteria if he or she so desires. As an example, asuitable oral dosage form may encompass from about 5 to about 360 mgtotal daily dose, typically administered in one single dose or equallydivided doses. A more preferred range is from about 8 mg to about 60 mgtotal daily dose, and a most preferred range is from about 10 mg toabout 40 mg total daily dose. Additionally, the active ingredient(s) maybe administered in a solution, and, as an example, the daily doses setforth above may be employed. In one embodiment, the active ingredient(s)may be added in appropriate amounts to a solution such that the solutioncomprises, for example, from about 0.1 mg/mL to about 10 mg/mL of theactive ingredient(s). It should be appreciated that daily doses otherthan those described above may be administered to a subject, asappreciated by an attending physician. Preferred active ingredients arethose as set forth herein, while especially preferred ingredientsinclude, for example,6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sufinyl]-1H-benzimidazole,in pure form,6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleessentially free of5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole,a composition comprising6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleand5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazolewherein said6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazolecomprises from about 96% to about 100% (w/w) of said composition and acomposition comprising6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleand5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleis present in an amount greater than about 9%, preferably 15%, and mostpreferably 18% (w/w) of said composition. For the method of improvingthe bioavailability of one or more active ingredients set forth below, acomposition comprising6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleand5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleis also preferred. Also preferred are unit dosage forms as taughtherein, particularly in the amount of total active ingredient of about 8mg to about 10 mg, about 16 mg to about 20 mg, and about 32 mg to about40 mg per dosage unit.

[0296] In another aspect, the present invention provides a method ofimproving the bioavailability of one or more active ingredient of thepresent invention in a subject (e.g., mammal, particularly humans)comprising administering to a subject in need of such treatment atherapeutically effective amount of at least one active ingredient,composition thereof, or formulation thereof as described above, and atleast one cyclodextrin. This method may be carried out in accordancewith any of the techniques set forth herein, including employing,without limitation, any of the recited dosage forms, particularly in theunit dosages set forth herein. For the purposes of the invention, theterm “bioavailability” is defined as the total amount of activeingredient systematically available over time. Bioavailability may bedetermined by measuring total systemic active ingredient concentrationsover time after administration of such active ingredient(s) of thepresent invention either singularly or in comparison withbioavailability after administration of a conventional omeprazoleformulation (e.g., Prilosec®). As an example, improved bioavailabilitymay be defined as the Area Under the Curve (AUC). AUC is the integratedmeasure of systemic active ingredient concentrations over time in unitsof mass-time/volume. Following the administration of an activeingredient dose, the AUC from the time of dosing to the time when noactive ingredient remains in the body, is a measure of the exposure ofthe subject to the active ingredient or, in some cases, the activemolecule which is a metabolite of an active ingredient. In a preferredembodiment, this method typically allows for an increase in AUC of about20 percent or greater relative to a conventional omeprazole formulation.In another embodiment, the method allows for an increase in C_(max) of asubject of about 25 percent or greater relative to a conventionalomeprazole formulation.

[0297] The following examples are intended to illustrate the invention,and are not to be construed as limiting the scope of the invention. Forthe purposes of the examples, the phrase “(5)6-methoxy2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole”refers to a combination of, preferably a co-crystallized mixture, (withor without an amount of amorphous compounds), of5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleand6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole,each as determined and referenced herein.

EXAMPLE 1 Preparation of Essentially Pure6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole

[0298] Approximately 850 mL of methanol was placed in a 1 liter glassbottle with a screw cap. The solution was saturated by dissolvingapproximately 10.5 g of(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole,and the resulting solution was stirred. Once the solution was saturated,an additional 17 g of(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolewas added to the saturated solution to create a suspension. The cap wassealed and the saturated suspension was allowed to stir and equilibratefor about four days.

[0299] After four days, the suspension was filtered through a paperfilter and then washed with a small amount of methanol. The supernatantwas returned to the 1 liter glass bottle and an additional 10 g of(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolewas added to the saturated solution. The procedure was repeated tocreate an additional sample. All samples are shown to be essentiallypure6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleby Raman spectroscopy. This procedure has also been successfully carriedout using ethanol.

EXAMPLE 1a Preparation of Pure6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole

[0300] To a 1000 mL glass bottle having a screw cap having about 300 mLof methanol was added 1.93 g of sodium hydroxide pellets. The solutionwas stirred until such pellets dissolved, and omeprazole API was addeduntil a heavy suspension was formed. The solution was capped and allowedto sit at ambient temperature, for four days, then filtered using vacuumfiltration and a paper filter. The resulting solid was washed withthree, 50 mL portions of methanol, then placed in a vacuum oven to dryat ambient temperature. The title compound was removed after drying for24 hours, and the purity confirmed by FT-Raman spectroscopy.

EXAMPLE 2 Preparation of Essentially Free6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole

[0301] To a 50 mL beaker was added about 1 g of(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleto 30 mL of dimethylformamide (DMF). Additional(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolewas added to the resulting solution until a suspension of the materialwas formed. The solution was stirred for approximately 10 minutes, andthen filtered through a 0.45 μm Poly(tetrafluoroethylene) (PTFE) orNylon filter. The resulting saturated solution was placed in a shallowpetri dish, covered and stored under refrigerated conditions(approximately 5° C.) with a humidity range of about 0 to 50 percentuntil crystals formed (between 4-6 days). The identity of the titlecompound is confirmed by single crystal x-ray diffraction and Ramanspectroscopy, and shown to contain between about 96 and 98 percent (w/w)of the6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleand between about 2 and 4 percent (w/w) of5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole.

EXAMPLE 3 Preparation of(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole

[0302] The procedure set forth in Example 2 is repeated except thatethanol is employed as a solvent in place of DMF and the resultingstructure is shown by various X-ray crystal diffraction and/or Ramanspectroscopy to contain between about 82 and 85 percent (w/w) of6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleand between about 15 and 18 percent (w/w) of 5-methoxy2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole.

EXAMPLE 4 Preparation of5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleisomers

[0303] To a 50 mL beaker was added about 1 g of5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleto 30 mL of DMF. Additional5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolewas added to the resulting solution until a suspension of the materialwas formed. The solution was stirred for approximately 10 minutes, andthen filtered through a 0.45 μm PTFE or Nylon filter. The resultingsaturated solution was placed in a shallow petri dish, covered, andstored at ambient temperature and a humidity range of about 0 to 50percent until crystals formed (between 1-2 days). The identity of thetitle compound is confirmed by single crystal x-ray diffraction and/orRaman spectroscopy. The resulting structure was determined to containabout 93 percent (w/w) of the6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleand about 7 percent (w/w) of the5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole.

EXAMPLE 5 Preparation of5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleisomers

[0304] To a 50 mL beaker was added about 1 g of5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl-methyl]sulfinyl]-1H-benzimidazoleto 30 mL of methylene chloride. Additional5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolewas added to the resulting solution until a suspension of the materialwas formed. The solution was stirred for approximately 10 minutes, andthen filtered through a 0.45 μm PTFE or Nylon filter. The resultingsaturated solution. was placed in a beaker, covered, and stored underrefrigerated conditions (approximately 5° C.) until crystals formed(between 1-2 days). The identity of the title compound is confirmed bysingle crystal x-ray diffraction and/or Raman spectroscopy. Theresulting material was determined to contain between about 84 and 88percent (w/w) of the6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleand between about 12 and 16 percent (w/w) of the5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole.

EXAMPLE 6 Preparation of5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleisomers

[0305] To a 50 mL beaker was added about 1 g of5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleto 25 mL of acetone. Additional5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolewas added to the resulting solution until a suspension of the materialwas formed. The solution was stirred for approximately 5 minutes, andthen filtered through a 0.45 μm PTFE or Nylon filter. The resultingsaturated solution was placed in a 50 mL beaker, covered, and stored atambient temperature and a humidity range of about 0 to 50 percent untilcrystals formed (between 1-2 days). The identity of the title compoundis confirmed by single crystal x-ray diffraction and/or Ramanspectroscopy. The resulting material was determined to contain about 86percent (w/w) of the6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleand about 14 percent (w/w) of the5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole.

EXAMPLE 7 Preparation of5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleisomers

[0306] The procedure set forth in Example 6 is repeated except that anACN/water mixture was used as a solvent in place of acetone. A similarcomposition of6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleand5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleresulted.

EXAMPLE 8 Preparation of5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleisomers

[0307] The procedure set forth in Example 6 is repeated except that ACNwas used as a solvent in place of acetone. A similar composition of6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleand5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleresulted.

EXAMPLE 9 Preparation of(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleisomers

[0308] To a 400 mL beaker was added about 5 g of(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleto 200 mL of ethanol. 1.0 mL of ammonium hydroxide was added to thissolution and additional5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolewas added to the resulting solution until a suspension of the materialwas formed. The solution was stirred for about 10 minutes, then filteredthrough a paper filter. The resulting saturated solution was placed intwo separate drying vessels, and stored in a fume hood at ambienttemperature until crystals formed (between 1-12 hours). The identity ofthe title compound was confirmed by single crystal x-ray diffraction.The resulting structure was determined to contain about 82 percent (w/w)of the6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleand about 18 percent (w/w) of the5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole.

EXAMPLE 10 Preparation of(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole

[0309](5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole(16.2 g; 0.0492 mol)) is reacted with m-chlorobenzoic acid (13.6 g;0.0537 mol) with CH₂Cl₂ acting as a solvent at a pH of 8.6. The pH ismaintained by the presence of KHCO₃ (5.6 g; 0.056 mol) acting as abuffer. The temperature is maintained at about 0° C. during theaddition. Diluted NaOH is added to a pH above 12 and the CH₂Cl₂ phase isseparated off. Dimethylformamide (4.7 g) is charged to the water phaseand the pH is kept above 9, whereupon crystals a mixture of(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleare formed. The crystals are filtered off and are washed with water andmethanol at a temperature of about 0° C. The washed crystals are thendried under vacuum and are found to predominantly contain6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole.

EXAMPLE 11 Preparation of the Sodium Salt of6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole

[0310] To a stirring suspension of 10 g (29 mmol) of(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazolein 200 mL of methyl ethyl ketone (MEK) in a 1L flask was added atambient temperature 6 mL of a 5 M aqueous sodium hydroxide solution. Tothat mixture was added 200 mL of toluene; After approximately 7 minutes,the mixture became a clear solution. Approximately 2 minutes after that,the mixture became, turbid again. This mixture was allowed to stir atambient temperature overnight. The following morning, several crystals.of8-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazolesodium salt were added to act as seed crystals. Within a few minutes theproduct began to precipitate. After approximately 1 hour, the productwas isolated by vacuum filtration through filter paper on a ceramicBuchner funnel and rinsed with 25 mL of diethyl ether. The resultingsolids were allowed to air-dry for 24 hours.

EXAMPLE 12 Preparation of the Sodium Salt of6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole

[0311] To a flask containing 20mL of methanol was slowly added withstirring 580 mg (14.48 mmol) of 60% sodium hydride dispersed in mineraloil. The resulting cloudy mixture was vacuum filtered through aglass-fiber filter paper to yield a clear solution. To this clearsolution was added with stirring 5 g (14.48 mmol) of6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole.After approximately 5 minutes of stirring, the solution became clear.The stirring was stopped, the flask was covered and set aside. Afterapproximately 5 minutes, crystals began to form. The mixture was placedin a 5° C.-refrigerator overnight. The next day, the solids wereisolated by vacuum filtration to give approximately 5 g of the desiredproduct as a white, crystalline powder.

EXAMPLE 13 Preparation of the Sodium Salt of6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole

[0312] To a stirring solution of 5 g (14.48 mmol) of(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazolein 50 mL of dimethyl formamide (DMF) in a 100 mL beaker was slowly addedat ambient temperature 580 mg (14.48 mmol) of 60% sodium hydridedispersed in mineral oil. Once all the sodium hydride was added, themixture was allowed to stir for an additional 10 minutes. The solutionwas vacuum filtered through filter paper on a ceramic Buchner funnel. A20 mL portion of the resulting solution was placed in a 250 mLround-bottom flask, diluted with 50 mL of toluene and concentrated underreduced pressure at 20° C. (2 times), followed by 50 mL oftetrahydrofuran (1 time). The resulting solids were dried 18 hours atambient temperature in vacuo to yield the desired product as anoff-white, crystalline powder. The powder was recrystallized frommethanol by placing a filtered, saturated solution into the 5° C.refrigerator for several days, until crystals were present.

EXAMPLE 14 Preparation of the Sodium Salt of6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole

[0313] To a stirring suspension of 5 g (14.48 mmol) of(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazolein 50 mL of tetrahydrofuran (THF) in a 100 mL beaker was slowly added atambient temperature 580 mg (14.48 mmol). of 60% sodium hydride dispersedin mineral 1.5 oil. Once all the sodium hydride was added, the mixturewas allowed to stir for an additional 20 minutes. The solids wereisolated by vacuum filtration through filter paper on a ceramic Buchnerfunnel and rinsed with a small amount of THF. The solids were dried 18hours at ambient temperature in vacuo to yield 4.8 g (90%) of thedesired product as an off-white, crystalline powder. The powder wasrecrystallized from 1:1 methanol:ethyl acetate by placing a filtered,saturated solution into the 5° C. refrigerator for several days, untilcrystals were present.

EXAMPLE 15 Preparation of the Sodium Salt of(−)(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole

[0314] To a stirring solution of 1.5 g (4.33 mmol) of(−)-(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sufinyl]-1H-benzimidazolein 15 mL of tetrahydrofuran (THF) in a 50 mL beaker was slowly added atambient temperature 173 mg of 60% sodium hydride dispersed in mineraloil. Once all the sodium hydride was added, the mixture was allowed tostir for 45 minutes at ambient temperature. An additional 15 mL of THFwas added to the mixture and was allowed to stir for an additional 20minutes. The precipitated solids were isolated by vacuum filtrationthrough filter paper on a ceramic Buchner funnel, rinsed with 40 mL ofthe THF and dried 18 hours at ambient temperature in vacuo to yield 1.3g (81 percent) of the desired product as an off-white powder.

EXAMPLE 16 Preparation of(+)-(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazolesodium salt

[0315] To a stirring suspension of 650 mg (1.89 mmol) of(+)-(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazolein 6.5 mL of methyl ethyl ketone (MEK) in a 50 mL flask was added atambient temperature 0.39 mL of a 5M aqueous sodium hydroxide solution.To that mixture was added 13 mL of toluene. The resulting mixture wasturbid, so an additional 6.5 mL of MEK was added and the mixture becamea clear, yellow solution. This mixture was allowed to stir at ambienttemperature overnight The following morning, several crystals of6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sufinyl]-1H-benzimidazolesodium salt were added to act as seed crystals, but no product crystalsformed. A stream of dry nitrogen gas was blown over the mixture to beginremoving the solvent. After approximately 10 minutes, the productprecipitated. The solids were isolated by vacuum filtration and washedwith a small amount of diethyl ether. The solids were then placed into avacuum desiccator to remove the last traces of ether, to yieldapproximately 500 mg of the desired product as an off-white powder.

EXAMPLE 17 Preparation of(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazolemagnesium salt tetrahydrate

[0316] 1.65 g of6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazolesodium salt was dissolved in 30 mL of water. To the stirring solutionwas added 0.47 g of magnesium chloride dissolved in 20 mL of water.Immediately upon the addition of the magnesium chloride solution a whitepowder precipitated. The suspension was allowed to stir for 5 minutes,and then the product was isolated by vacuum filtration. The solids werethen placed into a vacuum desiccator overnight to give the desiredproduct as a white powder. A small portion of the powder was dissolvedin methanol at about 75 mg/mL, filtered and diluted with a equal volumeof water. This solution was partially covered and set aside to slowlyevaporate. After approximately 5 days, crystals were isolated, analyzedby single crystal x-ray diffraction and shown to be the desired product.

EXAMPLE 18 Preparation of a Mixture of the (−) Enantiomers of(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole

[0317](5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole(4.0 g, 12.1 mmol) is suspended in toluene (12 mL). (−) DiethylD-tartrate (0.17 mL, 1.0 mmol) and titanium(IV) isopropoxide (0.15 mL,0.50 mmol) are added with stirring at 50° C. The mixture is stirred at50° C. for 50 minutes and then N,N-diisopropylethylamine (0.085 mL, 0.50mmol) is added at ca. 30° C. Then, cumeme hydroperoxide (83%, 2.1 mL,11.9 mmol) is added and the mixture is stirred for 15 minutes at 30° C.The resulting mixture contains the (−) enantiomers of (5)6methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole.

EXAMPLE 19 Preparation of a Mixture of the (+) Enantiomers of(5)6-methoxy-2-[[(4-methoxy-3,3-dimethyl-2-pyridinyl) methylsulfinyl]-1H-benzimidazole

[0318] (+) Diethyl L-tartrate (1.71 mL, 10 mmol) and titanium(IV)isopropoxide (1.5 ml, 5 mmol) are dissolved in methylene chloride (50mL). Water (90 μl. 5 mmol) is added with stirring and the resultantmixture is heated to reflux for one hour. The mixture is cooled to roomtemperature. Thereafter,(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thiol-1H-benzimidazole(1.65 g, 5 mmol) and cumene hydroperoxide (80%, 1.5 g, 5.5 mmol) areadded at room temperature. The solution is stirred at room temperaturefor 90 minutes. The final product provides(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoles.

EXAMPLE 20 Preparation of(−)-(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazolemagnesium salt

[0319] To a nitrogen-purged flask containing 50 mL of methanol was addedwith stirring 0.11 g (4.5 mmol) of magnesium metal, followed by acatalytic amount (˜0.5 mL) of methylene chloride. This mixture washeated to 40° C. for hours, then removed from the heat an allowed tocool to ambient temperature. To the cloudy, stirring solution was addedapproximately 2 g of(−)-5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole.The flask was purged well with nitrogen, sealed and allowed to stir atambient temperature overnight. Approximately 0.1 mL of water was thenadded to the reaction mixture and allowed to stir for 30 minutes toprecipitate inorganic magnesium salts. The mixture was then vacuumfiltered, and the filtrate reduced to approximately 20% of the originalvolume under reduced pressure. To that resulting solution was added withstirring 100 mL of acetone. After approximately 5 minutes of stirring, aprecipitate began to form. The mixture was allowed to stir for anadditional 30 minutes. The solids were isolated by vacuum filtration andwashed with some fresh acetone. The solids were allowed to air dry toyield 640 mg of the desired product.

EXAMPLE 21-29 Preparation of6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazolefrom mixtures of 5- and 6-methoxy benzimidazoles

[0320] Compositions which are formed in Examples 3-10 are subjected tothe procedure set forth in Example 1. Pure 6-methoxy compounds werethereafter obtained from this procedure.

EXAMPLE 30-33 Preparation of6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazolefrom mixtures of 5- and 6-methoxy benzimidazoles

[0321] Compositions which are formed in Examples 15-17 and 20 aresubjected to the procedure set forth in Example 1. Pure salts of the6-methoxy compounds were thereafter obtained from this procedure.

EXAMPLE 34 Determination of Percentage of Co-Crystallized 5- and6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1Hbenzimidazole isomers

[0322] Typically, a single crystal X-ray diffraction was used todetermine the percentage of 5- and6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sufinyl]-1H-benzimidazoleisomers in an API. Without being bound to theory, it is believed that acrystalline material diffracts X-rays due to the constructive anddestructive interference of the scatter of X-rays from the atoms of themolecule within the crystal lattice. The intensity and positions of thediffraction spots produced by the crystal is capable of generatingstructural information about the locations of the atoms in the moleculeof a crystal.

[0323] In this instance, a single crystal of the material to be examinedis mounted at the end of a glass fiber. The crystal is aligned in thediffractometer in a specific orientation. The diffraction spots aremeasured, then the crystal is rotated to the next position. The abovesequence is then repeated until thousands of individual diffractionspots are measured and recorded. The diffraction spots are then analyzedand the data phased to generate an electron density map from which amolecular structure of the molecule is uniquely determined. The X-raydiffraction data is generated using either a Nonius CAD4 diffractometeror a Nonius Kappa CCD diffractometer made commercially available byNonius Corporation of Delft, Netherlands. The diffraction data generatedfor the various batches of omeprazole API tested shows the molecularstructure of the drug present. It was determined from the data that thecrystal lattice contained various degrees of disorder of the 6- and5-methoxy isomers within the API. The two isomers were found toco-crystallize within a single crystal lattice. This co-crystallizationwithin the single lattice is believed to cause a distortion of the sixindependent unit cell parameters in relation to the amount of eachisomer present. The exact amount of 5-methoxy isomer present wasdetermined by a least-squares minimization of the data. A linearregression analysis of the cell constants to the percentage of the5-methoxy isomer present demonstrated good correlation coefficients.

[0324] In this example, the compounds were found to containpredominantly two diastereomers, namely the S_(xa)—R_(4q) andS_(xb)—R_(4z) derivatives. Such proposed behavior was not expected,since the manner in which the compounds were synthesized is believed tobe non-discriminatory towards selection of the R_(4q) or R_(4z) chiralplane with the corresponding S_(xa) or R_(4z) chiral center. Althoughnot intending to be bound by theory, structural analysis reveals thatthe 5- and 6-methoxy isomers crystallize through a center of inversionand are linked by hydrogen bonding from the amine hydrogens to thesulfoxide oxygens. The methoxy methyls are believed to be directedtowards the center of the bridged complex. Again not being bound bytheory, examination of the contact distances in the region where theother methoxy methyl may reside reveals that there may not be adequatespace within the lattice for the other diastereomer (S_(xa)—R_(4z) andS_(xb)—R_(4q)) to co-exist. The oxygen atom of the methoxy is observedto sit only about 3.6 Å from 4 other non-hydrogen atoms and 3.2 Å from 2hydrogen atoms of an adjoining molecule of omeprazole. Normal VanDerWaals contact distances are typically about 3.7 Å for non-hydrogenatoms.

EXAMPLE 35 Preparation of(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole

[0325] To a 50 mL beaker was added about 1 g of(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sufinyl]-1H-benzimidazoleto 30 mL of dimethylformamide (DMF). Additional(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolewas added to the resulting solution until a suspension of the materialwas formed. The solution was stirred for approximately 10 minutes, andthen filtered through a 0.45 μm Poly(tetrafluoroethylene) (PTFE) orNylon filter. The resulting saturated solution was placed in a shallowpetri dish, covered and stored under refrigerated conditions(approximately 5° C.) and a humidity range of approximately 50 to 90percent until crystals formed (between 4-7 days). The identity of thetitle compound is confirmed by single crystal x-ray diffraction and/orRaman spectroscopy. The resulting material was shown to contain betweenabout 85 and 89 percent (w/w) of the6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleand between about 11 and 15 percent (w/w) of5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole.

EXAMPLE 36 Preparation of(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole

[0326] To a 50 mL beaker was added about 1 g of(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleto 30 mL of acetone. Additional(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolewas added to the resulting solution until a suspension of the materialwas formed. The solution was stirred for approximately 10 minutes, andthen filtered through a 0.45 μm Poly(tetrafluoroethylene) (PTFE) orNylon filter. The resulting saturated solution was placed in a shallowpetri dish, covered and stored under refrigerated conditions(approximately 5° C.) and a humidity range of approximately 50 to 90percent until crystals formed (between 1-2 days). The identity of thetitle compound is confirmed by single crystal x-ray diffraction and/orRaman spectroscopy. The resulting material was shown to contain betweenabout 79 and 82 percent (w/w) of the6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleand between about 18 and 21 percent (w/w) of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole.

EXAMPLE 37 Preparation of(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole

[0327] To a 50 mL beaker was added about 1 g of(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sufinyl]-1H-benzimidazoleto 30 mL of methylene chloride. Additional(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sufinyl]-1H-benzimidazolewas added to the resulting solution until a suspension of the materialwas formed. The solution was stirred for approximately 10 minutes, andthen filtered through a 0.45 μm Poly(tetrafluoroethylene) (PTFE) orNylon filter. The resulting saturated solution was placed in a shallowpetri dish, covered and stored under refrigerated conditions(approximately 5° C.) and a humidity range of approximately 50 to 90percent until crystals formed (between 1-2 days). The identity of thetitle compound is confirmed by single crystal x-ray diffraction and/orRaman spectroscopy. The resulting material was shown to contain betweenabout 81 and 86 percent (w/w) of the6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleand between about 14 and 19 percent (w/w) of5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole.

EXAMPLE 38 Preparation of(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole

[0328] To a 50 mL beaker was added about 1 g of(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleto 30 mL of acetonitrile. Additional(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolewas added to the resulting solution until a suspension of the materialwas formed. The solution was stirred for approximately 10 minutes, andthen filtered through a 0.45 μm Poly(tetrafluoroethylene) (PTFE) orNylon filter. The resulting saturated solution was placed in a shallowpetri dish, covered and stored under refrigerated conditions(approximately 5° C.) and a humidity range of approximately 50 to 90percent until crystals formed (between 1-2 days). The. identity of thetitle compound is confirmed by single crystal x-ray diffraction and/orRaman spectroscopy. The resulting material was shown to contain betweenabout 88 and 92 percent (w/w) of the6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleand between about 8 and 12 percent (w/w) of5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole.

EXAMPLE 39 Preparation of(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole

[0329] To a 50 mL beaker was added about 1 g of(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleto 30 mL of methanol. Additional(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolewas added to the resulting solution until a suspension of the materialwas formed. The solution was stirred for approximately 10 minutes, andthen filtered through a 0.45 μm Poly(tetrafluoroethylene) (PTFE) orNylon filter. The resulting saturated solution was placed in a shallowpetri dish, covered and stored under refrigerated conditions(approximately 5° C.) and a humidity range of 1.5 approximately 50 to 90percent until crystals formed (between 1-3 days). The identity of thetitle compound is confirmed by single crystal x-ray diffraction and/orRaman spectroscopy. The resulting material was shown to contain betweenabout 84 and 86 percent (w/w) of the6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleand between about 14 and 16 percent (w/w) of5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole.

EXAMPLE 40 Preparation of(S)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole

[0330] To a 50 mL beaker was added about 1 g of(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleto 30 mL of dimethylformamide (DMF) containing 1 mL of ammoniumhydroxide. Additional(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolewas added to the resulting solution until a suspension of the materialwas formed. The solution was stirred for approximately 10 minutes, andthen filtered through a 0.45 μm Poly(tetrafluoroethylene) (PTFE) orNylon filter. The resulting saturated solution was placed in a shallowpetri dish, covered and stored under refrigerated conditions(approximately 5° C.) and a humidity range of approximately 50 to 90percent until crystals formed (between 24 days). The identity of thetitle compound is confirmed by single crystal x-ray diffraction and/orRaman spectroscopy. The resulting material was shown to contain betweenabout 88 and 92 percent (w/w) of the6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleand between about 8 and 12 percent (w/w) of5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sufinyl]-1H-benzimidazole.

EXAMPLE 41 Preparation of(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole

[0331] To a 50 mL beaker was added about 1 g of(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleto 30 mL of ethanol containing 1 mL of ammonium hydroxide. Additional(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolewas added to the resulting solution until a suspension of the materialwas formed. The solution was stirred for approximately 10 minutes, andthen filtered through a 0.45 μm Poly(tetrafluoroethylene) (PTFE) orNylon filter. The resulting saturated solution was placed in a shallowpetri dish, covered and stored under refrigerated conditions(approximately 5° C.) until crystals formed (between 2-6 days). Theidentity of the tile compound is confirmed by single crystal x-raydiffraction and/or Raman spectroscopy. The resulting material was shownto contain between about 85 and 88 percent (w/w) of the6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleand between about 12 and 15 percent (w/w) of5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole.

EXAMPLE 42 Preparation of Essentially Free6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole

[0332] To a 50 mL beaker was added about 1 g of(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleto 30 mL of dimethylformamide (DMF) containing 1 mL of ammoniumhydroxide. Additional(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolewas added to the resulting solution until a suspension of the materialwas formed. The solution was stirred for approximately 10 minutes, andthen filtered through a 0.45 μm Poly(tetrafluoroethylene) (PTFE) orNylon filter. The resulting saturated solution was placed in a shallowpetri dish, covered and stored under ambient conditions (approximately25° C.) and a humidity range of 0 to 50 percent until crystals formed(between 14 days). The identity of the title compound is confirmedby.single crystal x-ray diffraction and/or Raman spectroscopy. Theresulting material was shown to contain between about 96 and 98 percent(w/w) of the6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleand between about 2 and 4 percent (w/w) of5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole.

EXAMPLE 43 Preparation of(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole

[0333] To a 50 mL beaker was added about 1 g of(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleto 30 mL of a 75:25 mixture of ethanol:toluene. Additional(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolewas added to the resulting solution until a suspension of the materialwas formed. The solution was stirred for approximately 10 minutes, andthen filtered through a 0.45 μm Poly(tetrafluoroethylene) (PTFE) orNylon filter. The resulting saturated solution was placed in a shallowpetri dish, covered and stored under refrigerated conditions(approximately 5° C.) and a humidity range of approximately 50 to 90percent until crystals formed (between 4-12 days). The identity of thetitle compound is confirmed by single crystal x-ray diffraction and/orRaman spectroscopy. The resulting material was shown to contain betweenabout 82 and 90 percent (w/w) of the6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleand between about 10 and 18 percent (w/w) of5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole.

EXAMPLE 44 Preparation of(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole

[0334] To a 50 mL beaker was added about 1 g of(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleto 30 mL of chloroform. Additional(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolewas added to the resulting solution until a suspension of the materialwas formed. The solution was stirred for approximately 10 minutes, andthen filtered through a 0.45 μm. Poly(tetrafluoroethylene) (PTFE) orNylon filter. The resulting saturated solution was placed in a shallowpetri dish, covered and stored under refrigerated conditions(approximately 5° C.) and a humidity range of approximately 50 to 90percent until crystals formed (between 1-2 days). The identity of thetitle compound is confirmed by single crystal x-ray diffraction and/orRaman spectroscopy. The resulting material was shown to contain betweenabout 50 and 60 percent (w/w) of the6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleand between about 40 and 50 percent (w/w) of5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole.

EXAMPLES 45-112

[0335] Examples 45-112 generally pertain to formulations of theinvention comprising at least one active ingredient and at least onecyclodextrin. In these examples, bulk drug samples of5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolewere sourced from Uquifa, S A, Esteve Quimica, S. A., Cipla, Dr. Reddy'sLaboratories, Ltd. Solubility studies were performed using all of theabove materials. Lyophilization was performed using5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolefrom Dr. Reddy's Laboratories, Ltd. All other work was performed usingUquifa material including the manufacture of all clinical prototypes.Early development work, including solubility studies, lyophilization,spray drying, utilized Encapsin™ brand hydroxypropyl-beta-cyclodextrin(HPβCD) purchased from Amaizo located in Hammond, Indiana.Hydroxypropyl-beta-cyclodextrin (HPβCD) purchased from Wacker BiochemCorp of Adrian, Mich., was used in the manufacture of all clinicalprototypes.

[0336] Solubility studies were performed by the addition of a known massof5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole and/or HP CD to a given volume of solvent system.Solubilities were determined by observation, as the maximumconcentration at which5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolecompletely dissolved. Additionally, concentrations of5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleand HP CD at set molar ratios were solubilized in systems of high pH(adjusted as high as 12.2, with 1N NaOH), the pH was adjusted (using 2NHCl) in a stepwise downward manner until precipitation occurred.

[0337] In addition, the general definitions, manufacturer, andmanufacturer location for the following terms are provided:Acesulfame-k ® acetosulfam (sweetener) Hoechst Celanese; Chatam, NJAquaceat CPD 30 ® aqueous ethylcellulose FMC Corporation; dispensantPhiladelphia, PA Avicel PH 102 ® microcrystalline cellulose FMCCorporation; Philadelphia, PA Cab-o-Sil ® colloidal silicon dioxideCabot Corporation Rancho Santo Margarita, CA Eudragit L-30 D-55 ® type Bof aqueous latex Rohm America; (USPNF) dispersion of methylacrylicPiscataway, NJ acid polymer Eudragit L 30 D ® aqueous latex dispensionRohm America of F100 Piscataway, NJ Eudragit L-30 D-55 ® aqueous latexdispension Rohm America of methylacrylic acid Piscataway, NJ copolymertype C Fastflo ® lactose 316 Foremost Company; San Francisco, CA OpadryClean ® hydroxypropylmethyl- Colorcon; cellulose and polyethylene WestPoint, PA glycol (plasticizer) Opadry White ® hydroxypropylmethyl-Colorcon; cellulose polyethylene West Point, PA glycol (plasticizer),and titanium dioxide

EXAMPLE 45 Preparation of a Solution ContainingHydroxypropyl-Beta-Cyclodextrin and5(6)-Methoxy-2-[[(4-Methoxy-3,5-Dimethyl-2-Pyridinyl)-Methyl]sulfinyl]-1H-Benzimidazole

[0338] A solution containing hydroxypropyl-beta-cyclodextrin (HPβCD) and5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolewas prepared as follows. 30 g of HPβCD was weighed and added to 50 mL ofwater to dissolve therein. 5 g of5(6)-methoxy-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolewas thereafter added to the cyclodextrin solution. A 1M sodium hydroxidesolution was added until all of the5(6)-methoxy-2-[[(methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolewas in solution (approximate pH was 11.7). The pH was then adjusted to10.0 with 1M hydrochloric acid solution and water was added to achieve afinal volume of 100 mL. The resulting solution, prepared at 5 percent(w/v)5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleand 30 percent (w/w) HPβCD, was found to be stable for at least six dayswith little discoloration, as set forth in the following table. PercentActive Ingredient Day 5° C. Ambient Temperature 1 99.9% 101.0% 2 98.9% 97.7%* 3 98.8%   98.7%**

EXAMPLE 46 Lyophilization of a Solution ContainingHydroxypropyl-Beta-Cyclodextrin and5(6)-Methoxy-2-[[(4-Methoxy-3,5-Dimethyl-2-Pyridinyl)-Methyl]sulfinyl]-1H-Benzimidazole

[0339] A lyophilization procedure was carried out using 200 mL of asolution of combinedHPβCD/5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleof 17.5 percent (w/v) and a5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleto HPβCD mass ratio of 1:6.

EXAMPLE 47 Lyophilization of a Solution ContainingHydroxypropyl-Beta-Cyclodextrin and5(6)-Methoxy-2-(4-Methoxy-3,5-Dimethyl-2-Pyridinyl)-Methyl]Sulfinyl]-1H-Benzimidazole

[0340] A lyophilization procedure was carried out using 1345 mL of asolution of combinedHPβCD/5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleof 3 percent (w/v) and a5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleto HPβCD mass ratio of 1:6.8. The solution was prepared by dissolving5.1 g of5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolein 1 9 mL of a 40 percent solution of tetraethanolamine (TEA) andthereafter adding 1361 mL of a 2.3% (w/v) solution of HPβCD.

EXAMPLE 48 Spray Drying a Solution ContainingHydroxypropyl-Beta-Cyclodextrin and5(6)-Methoxy-2-[[(4-Methoxy-3,5-Dimethyl-2-Pyridinyl)-Methyl]sulfinyl]-1H-Benzimidazole

[0341] 2000 mL of a complexed solution of5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleand HPβCD was prepared according. to Example 45 with a combinedHPβCD/5(6)-methoxy-2-[[(4-methoxy-3,5dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole(w/v) of 17.5 percent and a5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleto HPβCD mass ratio of 1:6. This solution was spray dried using a SprayDrier, Model GB-21 made commercially available by Yamato located inTokyo, Japan.

EXAMPLE 49 Spray Granulation of a Solution ContainingHydroxypropyl-Beta-Cyclodextrin and5(6)-Methoxy-2-[[(4-Methoxy-3,5-Dimethyl-2-Pyridinyl)-Methyl]Sulfinyl]-1H-Benzimidazole

[0342] 2000 to 6000 mL of a complexed solution of5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sufinyl]-1H-benzimidazoleand HPβCD was prepared according to Example 41 with a combinedHPβCD/5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole(w/v) ranging from 17.5 to 35.0 percent and a5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleto HPβCD mass ratio of 1:6. The complexed solution was top sprayed ontolactose 316 in a MP-1 Multi Processor made commercially available byNiro-Aeromatic located in Columbia, Md. at product temperature of 40° C.and an initial spray rate of 11 g/min, with a total spray time of 8hours.

EXAMPLE 50 Compact Preparation of a Solid Material ContainingHydroxypropyl-Beta-Cyclodextrin and5(6)-Methoxy-2-[[(4-Methoxy-3,5-Dimethyl-2-Pyridinyl)-Methyl]Sulfinyl]-1H-Benzimidazole

[0343] Solid complexed material prepared according to the lyophilizationprocedure of Example 48 was used to prepare various compacts. Thecompacts were prepared in approximately 10 mg strengths. An excipientcompatibility study was carried out with the study. being set up as afractional factorial design with independent variables which include:complex type, type of bulking agent(lactose vs. mannitol), tablet size(120 mg, 140 mg, and 160 mg), and level of colloidal silicon dioxide (0percent 0.5 percent, and 1.0 percent). 70 mg of the complexed materialwas compressed into compacts of 120 mg, 140 mg, and 160 mg containing 20percent Avicel PH 102®, 2.0 percent Acesulfame-K, and either Lactose 316or granular mannitol as the bulking agent. Compacts were prepared withand without Cab-O-Sil L90®. These materials were sieved, blended, andpressed into compacts using 9/32″, plain, smooth, concave tolling on aKorsch PH 100 Tablet Press made commercially available by Korsch PressenGmbH of Berlin, Germany, turned manually.

EXAMPLE 51 Compact Preparation of a Solid Material ContainingHydroxypropyl-Beta-Cyclodextrin and5(6)-Methoxy-2-[[(4-Methoxy-3,5-Dimethyl-2-Pyridinyl)-Methyl]Sulfinyl]-1H-Benzimidazole

[0344] The procedure according to Example 50 was repeated using thesolid complexed material prepared according to the lyophilizationprocedure of Example 47.

EXAMPLES 52-75 Tablet Preparation of a Solid Material ContainingHydroxypropyl-Beta-Cyclodextrin and5(6)-Methoxy-2-[[(4-Methoxy-3,5-Dimethyl-2-Pyridinyl)-Methyl]Sulfinyl]-1H-Benzimidazole

[0345] These examples were carded out with solid complexed material atan5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleto HPβCD mass ratio of 1:6. Three prototype cores were prepared atapproximately 10 mg strengths of5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolefrom both sprayed onto lactose and lyophilization complex material(complex without TEA). This material was milled with a Quadro Comil(0.024 inch round screen) and combined with either Lactose 316 or AvicelPH 102, Acesulfame-K, (all prescreened through a #20 screen) and blendedin a 4-quart v-blender for 9 minutes (3 without intensifier, 3 withintensifier, and 3 without intensifier). Magnesium stearate was screenedthrough a #20 screen, added to the blend and blended for 2 minutes. Theblends were transferred to a Korsch PH100 or Key DB-16 tablet press andcompressed to a target weight of 160 mg with a target hardness ofapproximately 8 to 10 kP, using 9/32 inch round plain/plain concavetooling. Each of the core tablets was coated in a MP-1 MultiProcessor-made commercially available by Niro-Aeromatic of Columbia, Md.with a Wurster column insert. Tablets were undercoated with Opadry Clear(Colorcon YS-1-7472). After drying, a portion of each core prototype wascoated with a solution containing Eudragit L-30 D-55 or Aquacoat CPD-30.Prototype formulas and coating solutions are set forth in the foregoingtables. The prototypes were prepared at 20 mg strengths from a sprayedon lactose complex using Lactose 316 as the bulking agent. Tablets weremanufactured as described above and undercoated with Opadry White®(Colorcon YS-1-7003). After drying, core prototypes were coated with asolution containing Eudragit L-3.0 0-55.

[0346] Stability sample packages for initial prototypes consisted of 10mg and 20 mg tablets contained in a 60 cc white HOPE bottle, with apolypropylene cap with an induction seal and polyester coil. Bottleswere stored at 40° C. with 75 percent relative humidity, 25° C. with 60percent relative humidity and 5° C. Prototype Formulas 10 mg core 20 mgcore tablets tablets Formulation A B C K L M Lyophilization 43.75%Complex Sprayed on 87.50% 87.50% 50.90% 95.80% 95.80% Lactose Lactose316 32.75%  9.75% 46.35%  1.45%  1.45% Avicel PH102 20.00%  9.75%Acesulfame K  2.00%  2.00%  2.00%  2.00%  2.00%  2.00% Magnesium  0.50% 0.50%  0.50%  0.50%  0.50%  0.50% Stearate Cabosil  1.00%  0.25%  0.25% 0.25%  0.25%  0.25% Total   100%   100%   100%   100%   100%   100%

[0347] Prototype Formulas Formulation H D E F G mg/ mg/tablet mg/tabletmg/tablet mg/tablet tablet Core Component Active 10.0 10.0 10.0 10.010.0 Ingredient HP CD 60.0 60.0 60.0 60.0 60.0 Lactose 316 52.4 85.685.6 52.4 85.6 Avicel PH 102 32.0 32.0 Acesulfame K 3.2 3.2 3.2 3.2 3.2Magnesium 0.8 0.8 0.8 0.8 0.8 Stearate Colloidal 1.6 0.4 0.4 1.6 0.4Silicon Dioxide Core Total 160 160 160 160 160 Coating Component OpadryClear 4.8 4.8 4.8 4.8 9.6 Eudragit 16.8 24.0 24.0 L 30 D 55 Aquacoat CPD9.1 17.6 Talc 16.8 24.0 24.0 Triethyl 3.4 4.8 1.3 1.9 3.5 Citrate Total(mg) 201.8 217.6 214.1 175.8 190.7 Formulation I J N O mg/tabletmg/tablet mg/tablet mg/tablet Core Component Active 10.0 10.0 20.0 20.0Ingredient HP CD 60.0 60.0 142.9 Lactose 316 70.0 52.4 143.6 2.5 AvicelPH 102 15.6 32.0 Acesulfame K 3.2 3.2 3.4 3.4 Magnesium 0.8 0.8 0.9 0.9Stearate Colloidal 0.4 1.6 0.4 0.4 Silicon Dioxide Croscarmellose 1.7Sodium Core Total 160 160 170 170 Coating Component Opadry Clear 10.48.0 Opadry White 7.7 L 30 D 55 7.8 Aquacoat 19.0 15.6 CPD Talc 7.8Triethyl 3.7 3.0 1.5 Citrate Total (mg) 193.1 186.6 194.8

[0348] Coating Solution Formulations % Opadry Clear Coat Opadry Clear 5.0 Purified Water  95.0 Total 100.0 Opadry White Coating Opadry Clear 12.0 Purified Water  88.0 Total 100.0 Eudragit L30 D55 Eudragit L 30 D 30.3 Talc  9.1 Triethyl Citrate  1.8 Purified Water  58.8 Total 100.0Aquacoat CPD-30 Aquacoat CPD-30  55.7 Triethyl Citrate  3.3 PurifiedWater  41.0 Total 100.0

EXAMPLES 76-80 Preparation of Clinical Prototypes of a Solid MaterialContaining Hydroxypropyl-Beta-Cyclodextrin and5(6)-Methoxy-2-[[(4-Methoxy-3,5-Dimethyl-2-Pyridinyl)-Methyl]Sulfinyl]-1H-Benzimidazole

[0349] Clinical prototypes were manufactured by complexing5(65-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole(“active ingredient”) with HPβCD in solution and spraying the solutiononto lactose. The spray on lactose material was then blended withexcipients listed in the below table and compressed into core tablets.The mass ratios of5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleto HPβCD ranged from 1:4 to 1:20 with core tablet weights of 170 mg to550 mg, respectively as set forth in the table below. QuantitativeFormulas of Core Tablets 1:4 1:6 1:10 1:15 1:20 Component mg/tabletmg/tablet mg/tablet mg/tablet mg/tablet Active 20.0 20.0 20.0 20.0 20.0Ingredient HPβCD 80.0 120.0 200.0 300.0 400.0 Lactose 316 68.7 28.7 53.7228.7 128.7 Magnesium 0.9 0.9 0.9 0.9 0.9 Stearate Colloidal 0.4 0.4 0.40.4 0.4 Silicon Dioxide Total (mg) 170.0 170.0 275.0 550.0 550.0

[0350] All tablets were coated to a 4.5 percent total solids weight gainwith an Opadry White coating solution as a subcoat. After drying, a 10percent total solids weight gain from an Eudragit L 30 or D-55 coatingsolution was applied as an, enteric coat.

[0351] The stability of the sample packages for clinical prototypesconsisted of 20 mg tablets contained in a 60 cc white HDPE bottle, witha polypropylene CRC cap with an induction seal and a polyester coil.Bottles were stored at 40° C. with 75 percent relative humidity, 30° C.with 60 percent relative humidity, 25° C. with 60 percent relativehumidity, and 5° C.

EXAMPLES 81-85 Preparation of Clinical Prototypes of a Solid MaterialContaining Hydroxypropyl-Beta-Cyclodextrin and5(6)-Methoxy-2-[[(4-Methoxy-3,5-Dimethyl-2-Pyridinyl)-Methyl]Sulfinyl]-1H-Benzimidazole

[0352] The procedure according to Examples 76-80 was repeated exceptthat a 15 percent total solids weigh gain from an Eudragit FS 30 D(previously known as Eudragit Preparation 4110D) coating solution wasapplied as an enteric coat.

EXAMPLE 86 Solubility Assessment

[0353] The solubility of5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolewas assessed as a function of HPβCD concentration in water.5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolewas found to have an aqueous solubility in water of approximately 0.3mg/mL (0.9 mM). In general, the solubility of the active ingredient isinfluenced by solution pH. Solubility was found to increase linearly asa function of HPβCD concentration.

EXAMPLE 87 Solubility Assessment

[0354] The procedure according to Example 86 was repeated except thatwater with a borate buffer (pH of 8) was employed. Solubility was foundto increase linearly as a function of HPβCD concentration.

EXAMPLE 88 Solubility Assessment

[0355] The procedure according to Example 86 was repeated except thatwater with a phosphate buffer (pH of 11) was employed. Solubility wasfound to increase linearly as a function of HPβCD concentration.

EXAMPLE 89-98 Prototypes of5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleand HPβCD

[0356] Prototype formulations of 10 mg cores5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole(“active ingredient”) were prepared using either lactose or Avicel asthe bulking agent Formulations are presented in the table set forth inExample 52-75 under “Prototype Formulations”. Physical characterizationsare presented in the table hereinbelow. No significant differences inprocessing were observed for any of the formulations. All formulas werecompressed to approximately 7 kP hardness, containing about 4.6 percentmoisture, and disintegrated in less than 11 minutes. PhysicalCharacteristics of Initial 10 mg Prototypes 10 mg formulations of ActiveIngredient Hardness Formulation Weight (g) Thickness (in) (kP)Disintegration* (min) Moisture (%) A 0.1576 0.152 7.0 10:35 4.63 (0.005)(0.004) (0.47) (:16) B 0.163  0.153 6.6 8:01 4.73 (0.004) (0.003) (0.71)(:15) C 0.1649 0.156 6.8 8:56 4.65 (0.003) (0.002) (0.50) (:20) D 0.1985NT NT 26:29, SIF 3.3  (0.005) (:49) E 0.2042 NT NT 30:21, SIF 3.74(0.006) (:37) F 0.1984 NT NT 25:05, SIF 3.8  (0.004) (:40) G 0.1755 NTNT NT NT (0.004) H 0.182 NT NT 12:28, SIF 4.03 (0.005) (:50) I 0.1922 NTNT 15:50, SIF 4.24 (0.005) (:55) J 0.1826 NT NT 15:22, SIF 4.2  (0.003)(:31) K 0.1582 0.139 11.5  10:20 4.88 (0.001) (0.0005) (2.7) (:29)

EXAMPLES 95-101 Prototypes of5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleand HPβCD

[0357] Initial 20 mg core prototypes were manufactured with only lactoseas a bulking agent. They were compressed with mean hardnesses of 8.7 and16.5 kP (16.5 kP hardness required approximately 3000 lbs. ofcompression force). Mean disintegration times were less than 8 minutesfor both prototypes. Moisture levels were found to be 5.14 percent and5.64 percent as set forth in the below table.

[0358] An Opadry White undercoat with Eudragit L 30 D-55 as the entericcoat was used for the 20 mg tablets strengths. This system showed theleast or no discoloration and was used for clinical prototypes. PhysicalCharacteristics of Initial 20 mg Prototypes 20 mg Active IngredientFormulations Hardness Formulation Weight (g) Thickness (in) (kP)Disintegration* (min) Moisture (%) L 0.1683 0.151 8.7 8:00 5.14 (0.005)(0.0004) (1.1) (:22) (0.01) M 0.1674 0.155 16.5  7:21 5.64 (0.0007)(0.0005) (1.6) (:10) N 0.1713 NT 7.2 5:16 NT+ (0.002) (2.3) (:40) O0.1691 NT NT 10:56, SIF NT (:15)

EXAMPLES 102-106 Dissolution of Prototypes of5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleand HPβCD

[0359] Dissolutions of various prototypes set-forth in Examples 81-85were determined and compared against a Prilosec® formulation in the formof a capsule containing enteric coated granules. The Prilosecformulation contained no cyclodextrins. The dissolution was conductedfor 60 minutes in acid followed by 60 minutes in pH 7.4 buffer. Theprototypes of the invention having5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoleto HPβCO mass ratios of 1:4 and 1:6 displayed dissolution behaviorcomparable to the Prilosec® formulation.

EXAMPLES 107-109 Bioavailability Assessment (C_(max), AUC, and T_(max))

[0360] Fasted-state bioavailability studies were conducted in normalhealthy subjects (six subjects per study) comparing three formulationsof the present invention to Prilosec® in a 2-way crossover design. Allformulations were administered as a single 20 mg dose immediatelyfollowing an overnight fast. Blood was collected at 0.0, 0.5, 1.0, 1.5,2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 7.0, 8.0 hours in the study, withadditional collections being made at hours 10 and 12. The studies wereconducted comparing three 20 mg tablets to Prilosec. The comparisonconsisted of 6 different subjects, with three formulations containingactive ingredient to HPβCD mass ratios of 1:6, 1:6, 1:10, and coatingsof Eudragit FS3OD, L3OD, and L3OD, respectively (denoted respectively asformulations A, B, and C). The formulations of the invention generallydisplayed improved bioavailability relative to the innovator formulation(i.e., Prilosec) as set forth in the following table. BioavailabilityStudy Results Formulation C_(max)* AUC* T_(max) A +28%  +6% 5.8 hrs (vs2.0 for the innovator) B +14% +13% 2.2 hrs (vs 1.4 for the innovator) C+60% +11% 2.8 hrs (vs 2.4 for the innovator)

EXAMPLES 110-112 Bioavailability Assessment (C_(max), AUC, and T_(max))

[0361] The procedure according to Examples 107-109 was repeated exceptthat these studies was conducted in 47 subjects. 15 or 16 subjects perstudy received one of three 20 mg tablets containing active ingredientto HPβCD mass ratios of 1:4, 1:15, 1:20, denoted as formulations D, E,and F respectively. All tablets were coated with Eudragit L3OD. All 47subjects received Prilosec. Blood collections were not made at the 10and 12 hour marks.

[0362] The formulations of the invention generally displayed improvedbioavailability relative to the innovator formulation (i.e., Prilosec)as set forth in the following table. Bioavailability Study ResultsFormulation C_(max)* AUC* T_(max) D +116% +30% 2.0 hrs (vs 2.2 for theinnovator) E  +54% +19% 2.4 hrs (vs 2.0 for the innovator) F  +73% +23%1.9 hrs (vs 1.9 for the innovator)

[0363] The examples and embodiments as set forth in the detaileddescription are for illustrative purposes only and do not limit thescope of the invention as defined by the claims.

EXAMPLE 113 Enteric Coated Tablet

[0364] A formulation employing an active ingredient is made according tothe following recipe: g Core Material Active Ingredient 225 Mannitol1425 Hydroxypropyl cellulose 60 Microcrystalline cellulose 40 Anhydrouslactose 80 Sodium lauryl sulfate 5 Dibasic sodium phosphate dihydrate 8Purified water 350 Separating Layer Core material 300 Hydroxypropylcellulose 30 Talc 51 Magnesium stearate 4 Water 600 Enteric CoatingLayer Pellets covered with separating layer 279 Methacrylic acidcopolymer 140 Triethyl citrate 42 Mono-and diglycerides 7 Polysorbate 800.7 Water 300 Tablets Enteric coating layered pellets 352Microcrystalline cellulose 1,052 Sodium Stearyl fumarate 3

[0365] Sodium lauryl sulfate is dissolved in purified water to form agranulation liquid. The active ingredient along with the other dryingredients used in making the core are dry mixed. The granulationliquid is added to the powder mixture and the resulting mass is kneededand granulated to a proper consistency.

[0366] The wet mass is forced through an extruder equipped with screens.The extrudate is spheronized in a spheronizing apparatus. The corematerial is dried in a fluid bed dryer and classified into a suitableparticle range. The prepared core material is covered with a separatinglayer in a fluid bed apparatus with a hydroxypropyl methylcellulosesolution containing talc and magnesium stearate.

[0367] The enteric coating layer is sprayed onto the pellets coveredwith the separating layer from an aqueous dispersion of methacrylic acidcopolymer, mono- and diglycerides, triethyl citrate, and polysorbate ina fluid bed apparatus.

[0368] Enteric coating layered pellets, microcrystalline cellulose andsodium stearyl fumarate are mixed and compressed into tablets using arotary tableting machine.

EXAMPLE 114

[0369] Tablet A tablet is formed from the following ingredients:Ingredient g active ingredient 400-430 lactose, anhydrous 1,400-1,420polyvinylpyrrolodine 100  sodium carbonate, anhydrous 15 methylcellulose 12 distilled water 200  magnesium stearate 30

[0370] The active ingredient, lactose, polyvinylpyrrolidone, and sodiumcarbonate are homogenized and granulated by the addition of the methylcellulose and distilled water. The wet mass is dried in a fluidized beddrier using. an. inlet air temperature of +50° C. for 30 minutes. Thedried mixture is then forced through a sieve with an aperture of 0.5 mm.After mixing with magnesium stearate, the granulate is tableted on atableting machine using 6 mm punches. The tablet weight is 100 mg. Thetablet may optionally be coated with the separating layer and/or entericcoating as described in Example 113.

That which is claimed:
 1. A compound represented by the formula (Ia):

wherein: S_(x) represents a chiral sulfur atom comprising at least oneof the diastereomers represented by S_(xa) and S_(xb), wherein S_(xa) isthe (−) diasteromer and S_(xb) is the (+) diasteromer; R is alkoxy; R₁is selected from the group consisting of hydrogen, alkyl, halogen,carboalkoxy, alkoxy, and alkanoyl; R₂ is hydrogen or alkyl; and R₃, R₄,and R₅ may be the same or different and are each selected from the groupconsisting of hydrogen, alkyl, alkoxy, and alkoxyalkoxy, wherein when R₄is alkoxy and R₃ and R₅ are not hydrogen, the alkyl substituent of suchalkoxy group is selected from the group consisting of at least one ofthe diastereomers represented by R_(4q) and R_(4z), wherein R_(4q) isthe diastereomer and lies above the chiral plane; and R_(4z) is the (+)diastereomer and lies below the chiral plane; or one or morepharmaceutically acceptable salts, solvates, hydrates, or combinationsthereof.
 2. A compound according to claim 1, wherein diastereomers ofsaid compound represented by formula (Ia) are selected from the groupconsisting of: (a) S_(xa)—R_(4q); (b) S_(xa)—R_(4z); (c) S_(xb)—R_(4q);and (d) S_(xb)—R_(4z), or one or more pharmaceutically acceptable salts,solvates, hydrates, or combinations thereof.
 3. A composition comprisingtwo or more compounds according to claim 1, or one or morepharmaceutically acceptable salts, solvates, hydrates, or combinationsthereof.
 4. A composition according to claim 3, wherein each of said twoor more compounds comprises the same or different diastereomers selectedfrom the group consisting of: (a) S_(xa)—R_(4q) (b) S_(xa)—R_(4z); (c)S_(xb)—R_(4q); and (d) S_(xb)—R_(4z), or one or more pharmaceuticallyacceptable salts, solvates, hydrates, or combination thereof.
 5. Acomposition according to claim 4, wherein said salt thereof is one ormore alkaline metal salts.
 6. A pharmaceutical formulation comprising acomposition according to claim 4 and at least one pharmaceuticallyacceptable carrier, diluent, or excipient.
 7. A pharmaceuticalformulation according to claim 6, wherein said salt thereof is one ormore alkaline metal salts.
 8. A pharmaceutical formulation according toclaim 6, wherein said composition comprises6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole,or one or more pharmaceutically acceptable salts, solvates, hydrates, orcombination thereof.
 9. A pharmaceutical formulation according to claim8, wherein said salt thereof is one or more alkaline earth metal salts.10. A composition according to claim 4, wherein said composition isessentially free of compounds represented by formula (Ib):

wherein: S_(x) represents a chiral sulfur atom comprising at least oneof the diastereomers represented by S_(xa) and S_(xb), wherein S_(xa) isthe (−) diastereomer and S_(xb) is the (+) diastereomer; R is alkoxy; R₁is selected from the group consisting of hydrogen, alkyl, halogen,carboalkoxy, alkoxy, and alkanoyl; R₂ is hydrogen or alkyl; and R₃, R₄,and R₅ may be the same or different and are each selected from the groupconsisting of hydrogen, alkyl, alkoxy, and alkoxyalkoxy, wherein when R₄is alkoxy and R₃ and R₅ are not hydrogen, the alkyl substituent of suchalkoxy group is selected from the group consisting of at least one ofthe diastereomers represented by R_(4q) and R_(4z), wherein R_(4q) isthe (−) diastereomer and lies above the chiral plane; and R_(4z) is the(+) diastereomer and lies below the chiral plane; or one or morepharmaceutically acceptable salts, solvates, hydrates, or combinationsthereof of said compounds represented by formula (Ib).
 11. A compositionaccording to claim 10, wherein said salt thereof is one or more alkalinemetal salts.
 12. A pharmaceutical formulation comprising said two ormore compounds according to claim 10 and at least one pharmaceuticallyacceptable carrier, diluent, or excipient.
 13. A pharmaceuticalformulation according to claim 12, wherein said salt thereof is one ormore alkaline metal salts.
 14. A pharmaceutical formulation according toclaim 12, wherein said composition comprises6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole,or one or more pharmaceutically acceptable salts, solvates, hydrates, orcombination thereof.
 15. A pharmaceutical formulation according to claim14, wherein said salt thereof is one or more alkaline metal salts.
 16. Acomposition comprising: (a) one or more compounds represented by formula(Ia):

wherein: S_(x) represents a chiral sulfur atom comprising at least oneof the diastereomers represented by S_(xa) and S_(xb), wherein S_(xa) isthe (−) diastereomer and S_(xb) is the (+) diastereomer; R is alkoxy; R₁is selected from the group consisting of hydrogen, alkyl, halogen,carboalkoxy, alkoxy, and alkanoyl; R₂ is hydrogen or alkyl; and R₃, R₄,and R₅ may be the same or different and are each selected from the groupconsisting of hydrogen, alkyl, alkoxy, and alkoxyalkoxy, wherein when R₄is alkoxy and R₃ and R₅ are not hydrogen, the alkyl substituent of suchalkoxy group is selected from the group consisting of at least one ofthe diastereomers represented by R_(4q) and R_(4z), wherein R_(4q) isthe (−) diastereomer and lies above the chiral plane; and R_(4z) is the(+) diastereomer and-lies below the chiral plane, or one or morepharmaceutical acceptable salts, solvates, hydrates, or combinationsthereof, and (b) one or more compounds represented by formula (Ib):

wherein: S_(x) represents a chiral sulfur atom comprising at least oneof the diastereomers represented by S_(xa) and S_(xb), wherein S_(xa) isthe (−) diastereomer and S_(xb) is the (+) diastereomer; R is alkoxy; R₁is selected from the group consisting of hydrogen, alkyl, halogen,carboalkoxy, alkoxy, and alkanoyl; R₂ is hydrogen or alkyl; and R₃, R₄,and R₅ may be the same or different and are each selected from the groupconsisting of hydrogen, alkyl, alkoxy, and alkoxyalkoxy, wherein when R₄is alkoxy and R₃ and R₅ are not hydrogen, the alkyl substituent of suchalkoxy group is selected from the group consisting of at least one ofthe diastereomers represented by R_(4q) and R_(4z), wherein R_(4q) isthe (−) diastereomer and lies above the chiral plane; and R_(4z) is the(+) diastereomer and lies below the chiral plane, or one or morepharmaceutically acceptable salts, solvates, hydrates, or combinationsthereof of said composition.
 17. A composition according to claim 16,wherein R of each of said compounds represented by formulae (Ia) and(Ib) is the same alkoxy substituent and each of said substituents S_(x),R₂, R₃, R₄, and R₅ of each of said compounds represented by formulae(Ia) and (Ib) are the same, or one or more pharmaceutically acceptablesalts solvates, hydrates, or combinations thereof.
 18. A compositionaccording to claim 17, wherein said composition comprises a ratio ofcompounds represented by formulae (Ia) and (Ib), said ratio selectedfrom the group consisting of: (a) said compounds represented by formula(Ia) are present in a range from about 1 percent (w/w) to about 99percent (w/w) and said compounds represented by formula (Ib) are presentin a range from about 1 percent (w/w) to about 99 percent (w/w) suchthat the sum of the total percentage of such compounds represented byformulae (Ia) and (Ib) equals about 100 percent (w/w); (b) saidcompounds represented by formula (Ia) are present in a range from about96 percent (w/w) to about 99 percent (w/w) and said compoundsrepresented by formula (Ib) are present in a range from about 1 percent(w/w) to about 4 percent (w/w) such that the sum of the total percentageof such compounds represented by formulae (Ia) and (Ib) equals about 100percent (w/w); and (c) said compounds represented by formula (Ia) arepresent in a range from about 1 percent (w/w) to about 85 percent (w/w)and said compounds represented by formula (Ib) are present in a rangefrom about 15 percent (w/w) to about 99 percent (w/w) such that the sumof the total percentage of such compounds represented by formulae (Ia)and (Ib) equals about 100 percent (w/w), or one or more pharmaceuticallyacceptable salts, solvates, hydrates, or combinations thereof.
 19. Acomposition according to claim 18, wherein each of said compoundsrepresented by formulae (Ia) and (Ib) comprises the same or differentdiastereomers selected from the group consisting of: (a) S_(xa)—R_(4q);(b) S_(xa)—R_(4z); (c) S_(xb)—R_(4q); and (d) S_(xb)—R_(4z), or one ormore pharmaceutically acceptable salts, solvates, hydrates, orcombinations thereof.
 20. A composition according to claim 19, whereinsaid salt thereof is one or more alkaline metal salts.
 21. Apharmaceutical formulation comprising a composition according to claim19 and at least one pharmaceutically acceptable carrier, diluent orexcipient.
 22. A pharmaceutical formulation according to claim 21,wherein said salt is one or more alkaline metal salts.
 23. Apharmaceutical formulation according to claim 21, wherein said compoundsrepresented by formula (Ia) are6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole,or one or more pharmaceutically acceptable salt, solvate, hydrate, orcombination thereof, and said compounds represented by formula (Ib) are5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole,or one or more pharmaceutically acceptable salt, solvate, hydrate, orcombination thereof.
 24. A pharmaceutical formulation according to claim23, wherein said salt thereof is one or more alkaline metal salt.
 25. Acomposition according to claim 19, wherein said compounds represented byformulae (Ia) and (Ib) are, in part or in whole, co-crystallized.
 26. Acomposition according to claim 25, wherein said salt thereof is one ormore alkaline metal salts.
 27. A pharmaceutical formulation according toclaim 21 wherein said compounds represented by formulae (Ia) and (Ib)are, in part or in whole, co-crystallized.
 28. A pharmaceuticalformulation according to claim 27, wherein said salt thereof is one ormore alkaline metal salts.
 29. A pharmaceutical formulation according toclaim 23, wherein said compounds represented by formulae (Ia) and (Ib)are, in part or in whole, co-crystallized.
 30. A pharmaceuticalformulation according to claim 29, wherein said salt thereof is one ormore alkaline metal salts.
 31. A composition comprising a plurality ofcomplexes, wherein each complex comprises at least two molecules of acompound according to claim 1, with said compounds being the same ordifferent, or one or more pharmaceutically acceptable salts, solvates,hydrates, or combinations thereof, and at least one atom of a metalcation for each of said two molecules of said compound.
 32. Acomposition according to claim 31, wherein said composition optionallycomprises at least one solvent residue for each of said two molecules ofsaid compound.
 33. A pharmaceutical formulation comprising a compositionaccording to claim 32 and at least one pharmaceutically acceptablecarrier, diluent, or excipient.
 34. A composition according to claim 32,wherein said composition is essentially free of compounds represented byformula (Ib):

wherein: S_(x) represents a chiral sulfur atom comprising at least oneof the diastereomers represented by S_(xa) and S_(xb), wherein S_(xa) isthe (−) diastereomer and S_(xb) is the (+) diastereomer; R is alkoxy; R₁is selected from the group consisting of hydrogen, alkyl, halogen,carboalkoxy, alkoxy, and alkanoyl; R₂ is hydrogen or alkyl; and R₃, R₄,and R₅ may be the same or different and are each selected from the groupconsisting of hydrogen, alkyl, alkoxy, and alkoxyalkoxy, wherein when R₄is alkoxy and R₃ and R₅ are not hydrogen, the alkyl substituent of suchalkoxy group is selected from the group consisting of at least one ofthe diastereomers represented by R_(4q) and R_(4z), wherein R_(4q) isthe (−) diastereomer and lies above the chiral plane; and R_(4z) is the(+) diastereomer and lies below the chiral plane; or one or morepharmaceutically acceptable salts, solvates, hydrates, or combinationsthereof of said compounds represented by formula (Ib).
 35. Apharmaceutical formulation comprising a composition according to claim34 and at least one pharmaceutically acceptable carrier, diluent, orexcipient.
 36. A composition comprising plurality of complexes, whereineach complex comprises at least two of the same or different molecules,at a ratio of 1 to 1 of one molecule of a compound represented byformula (Ia):

wherein: S_(x) represents a chiral sulfur atom comprising at least oneof the diastereomers represented by S_(xa) and S_(xb), wherein S_(xa) isthe (−) diastereomer and S_(xb) is the (+) diastereomer; R is alkoxy; R₁is selected from the group consisting of hydrogen, alkyl, halogen,carboalkoxy, alkoxy, and alkanoyl; R₂ is hydrogen or alkyl; and R₃, R₄,and R₆ may be the same or different and are each selected from the groupconsisting of hydrogen, alkyl, alkoxy, and alkoxyalkoxy, wherein when R₄is alkoxy and R₃ and R₅ are not hydrogen, the alkyl substituent of suchalkoxy group is selected from the group consisting of at least one ofthe diastereomers represented by R_(4q) and R_(4z), wherein R_(4q) isthe (−) diastereomer and lies above the chiral plane; and R_(4z) is the(+) diastereomer and lies below the chiral plane, or one or morepharmaceutically acceptable salts, solvates, hydrates, or combinationsthereof, and one molecule of a compound represented by formula (Ib):

wherein: S_(x) represents a chiral sulfur atom comprising at least oneof the diastereomers represented by S_(xa) and S_(xb), wherein S_(xa) isthe (−) diastereomer and S_(xb) is the (+) diastereomer; R is alkoxy; R₁is selected from the group consisting of hydrogen, alkyl, halogen,carboalkoxy, alkoxy, and alkanoyl; R₂ is hydrogen or alkyl; and R₃, R₄,and R₅ may be the same or different and are each selected from the groupconsisting of hydrogen, alkyl, alkoxy, and alkoxyalkoxy, wherein when R₄is alkoxy and R₃ and R₅ are not hydrogen, the alkyl substituent of suchalkoxy group is selected from the group consisting of at least one ofthe diastereomers represented by R_(4q) and R_(4z), wherein R_(4q) isthe (−) diastereomer and lies above the chiral plane; and R_(4z) is the(+) diastereomer and lies below the chiral plane, or one or morepharmaceutically acceptable salts, solvates, hydrates, or combinationsthereof of said composition, and at least one atom of a metal cation foreach of said two molecules of said compounds represented by formulae(Ia) and (Ib).
 37. A composition according to claim 36, wherein saidcomposition optionally comprises at least one solvent residue for eachof said two molecules of said compounds represented by formula (Ia) and(Ib).
 38. A pharmaceutical formulation comprising a compositionaccording to claim 37 and at least one pharmaceutically acceptablecarrier, diluent, or excipient.
 39. A method of inhibiting gastric acidsecretions in mammals comprising administering to a mammal in need oftreatment a therapeutically effective amount of a pharmaceuticalformulation according to claim
 6. 40. A method according to claim 39wherein said salt thereof is one or more alkaline metal salts.
 41. Amethod of inhibiting gastric acid secretions in mammals comprisingadministering to a mammal in need of treatment a therapeuticallyeffective amount of a pharmaceutical formulation according to claim 8.42. A method according to claim 41 wherein said salt thereof is one ormore alkaline metal salts.
 43. A method of inhibiting gastric acidsecretions in mammals comprising administering to a mammal in need oftreatment a therapeutically effective amount of a pharmaceuticalformulation according to claim
 12. 44. A method according to claim 43,wherein said salt thereof is one or more alkaline metal salts.
 45. Amethod of inhibiting gastric acid secretions in mammals comprisingadministering to a mammal in need of treatment a therapeuticallyeffective amount of a pharmaceutical formulation according to claim 14.46. A method according to claim 45, wherein said salt thereof is one ormore alkaline metal salts.
 47. A method of inhibiting gastric acidsecretions in mammals comprising administering to a mammal in need oftreatment a therapeutically effective amount of a pharmaceuticalformulation according to claim
 21. 48. A method according to claim 47,wherein said salt thereof is one or more alkaline metal salts.
 49. Amethod of inhibiting gastric acid secretions in mammals comprisingadministering to a mammal in need of treatment a therapeuticallyeffective amount of a pharmaceutical formulation according to claim 23.50. A method according to claim 49, wherein said salt thereof is one ormore alkaline metal salts.
 51. A method of inhibiting gastric acidsecretions in mammals comprising administering to a mammal in need oftreatment a therapeutically effective amount of a pharmaceuticalformulation according to claim
 27. 52. A method according to claim 51,wherein said salt thereof is one or more alkaline metal salts.
 53. Amethod of inhibiting gastric acid secretions in mammals comprisingadministering to a mammal in need of treatment a therapeuticallyeffective amount of a pharmaceutical formulation according to claim 29.54. A method according to claim 53, wherein said salt thereof is one ormore alkaline metal salts.
 55. A method of inhibiting gastric acidsecretions in mammals comprising administering to a mammal in need oftreatment a therapeutically effective amount of a pharmaceuticalformulation according to claim
 33. 56. A method according to claim 55,wherein said salt thereof is one or more alkaline metal salts.
 57. Amethod of inhibiting gastric acid secretions in mammals comprisingadministering to a mammal in need of treatment a therapeuticallyeffective amount of a pharmaceutical formulation according to claim 35.58. A method according to claim 57, wherein said salt thereof is one ormore alkaline metal salts.
 59. A method of inhibiting gastric acidsecretions in mammals comprising administering to a mammal in need oftreatment a therapeutically effective amount of a pharmaceuticalformulation according to claim
 38. 60. A method according to claim 59,wherein said salt thereof is one or more alkaline metal salts.
 61. Aprocess for forming alkali and alkaline metal salts, in situ, ofcompositions according to claim 16 comprising preparing a solution ofone or more hydrides selected from the group consisting of alkali metalhydrides and alkaline metal hydrides, respectively, adding said hydridesolution to a solution of said compositions, and drying the resultingsolid material.
 62. A process according to claim 61, wherein saidalkaline metal hydride is selected from the group consisting of sodiumhydride and magnesium hydride.
 63. A process for forming alkali andalkaline metal salts of compositions according to claim 16 comprisingadding a solution of a solution of one or more hydrides selected fromthe group consisting of alkali metal hydrides and alkaline metalhydrides, respectively, to a suspension of a composition according toclaim 16, and drying the resulting solid material.
 64. A processaccording to claim 63, wherein said alkaline metal hydride is selectedfrom the group consisting of sodium hydride and magnesium hydride.